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  1. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  2. Tumor necrosis factor-alpha inhibitor treatment for sarcoidosis

    Directory of Open Access Journals (Sweden)

    José Luis Callejas-Rubio

    2008-12-01

    Full Text Available José Luis Callejas-Rubio, Lourdes López-Pérez, Norberto Ortego-CentenoUnit of Autoimmune Systemic Diseases, Hospital Clinico San Cecilio, Granada, SpainAbstract: Sarcoidosis is a chronic multisystem disease of unknown etiology, characterized by noncaseating granulomatous infiltration of virtually any organ system. Treatment is often undertaken in an attempt to resolve symptoms or prevent progression to organ failure. Previous studies have suggested a prominent role for tumor necrosis factor-alpha (TNF-α in the inflammatory process seen in sarcoidosis. TNF-α and interleukin-1 are released by alveolar macrophages in patients with active lung disease. Corticosteroids have proved to be efficacious in the treatment of sarcoidosis, possibly by suppressing the production of TNF-α and other cytokines. Three agents are currently available as specific TNF antagonists: etanercept, infliximab, and adalimumab. Although data from noncomparative trials suggest that all three have comparable therapeutic effects in rheumatoid arthritis, their effects in a granulomatous disease such as sarcoidosis are less consistent. In this review, current data on the effectiveness are summarized.Keywords: sarcoidosis, infliximab, etanercept, adalimumab, anti-TNA alpha

  3. Tumor Necrosis Factor Alpha: A Link between Neuroinflammation and Excitotoxicity

    Directory of Open Access Journals (Sweden)

    Gabriel Olmos

    2014-01-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a proinflammatory cytokine that exerts both homeostatic and pathophysiological roles in the central nervous system. In pathological conditions, microglia release large amounts of TNF-α; this de novo production of TNF-α is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. In addition, TNF-α can potentiate glutamate-mediated cytotoxicity by two complementary mechanisms: indirectly, by inhibiting glutamate transport on astrocytes, and directly, by rapidly triggering the surface expression of Ca+2 permeable-AMPA receptors and NMDA receptors, while decreasing inhibitory GABAA receptors on neurons. Thus, the net effect of TNF-α is to alter the balance of excitation and inhibition resulting in a higher synaptic excitatory/inhibitory ratio. This review summarizes the current knowledge of the cellular and molecular mechanisms by which TNF-α links the neuroinflammatory and excitotoxic processes that occur in several neurodegenerative diseases, but with a special emphasis on amyotrophic lateral sclerosis (ALS. As microglial activation and upregulation of TNF-α expression is a common feature of several CNS diseases, as well as chronic opioid exposure and neuropathic pain, modulating TNF-α signaling may represent a valuable target for intervention.

  4. Functional activities of receptors for tumor necrosis factor-alpha on human vascular endothelial cells.

    NARCIS (Netherlands)

    Paleolog, E.M.; Delasalle, S.A.; Buurman, W.A.; Feldmann, M.

    1994-01-01

    Tumor necrosis factor-alpha (TNF-alpha) plays a critical role in the control of endothelial cell function and hence in regulating traffic of circulating cells into tissues in vivo. Stimulation of endothelial cells in vitro by TNF-alpha increases the surface expression of leukocyte adhesion molecules

  5. T cells activate the tumor necrosis factor-alpha system during hemodialysis, resulting in tachyphylaxis

    NARCIS (Netherlands)

    van Riemsdijk, I C; Baan, C C; Loonen, E H; Knoop, C J; Navarro Betonico, G; Niesters, H G; Zietse, R; Weimar, W

    2001-01-01

    BACKGROUND: The immunosuppressive state of hemodialysis (HD) patients is accompanied by activation of antigen-presenting cell-derived cytokines, for example, tumor necrosis factor-alpha (TNF-alpha), which are required for T-cell activation. To test whether an activated TNF-alpha system results in im

  6. Tumor necrosis factor (TNF)-alpha, soluble TNF receptors and endometrial cancer risk : the EPIC study

    NARCIS (Netherlands)

    Dossus, Laure; Becker, Susen; Rinaldi, Sabina; Lukanova, Annekatrin; Tjonneland, Anne; Olsen, Anja; Overvad, Kim; Chabbert-Buffet, Nathalie; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Francoise; Teucher, Birgit; Chang-Claude, Jenny; Pischon, Tobias; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vasiliki; Valanou, Elisavet; Palli, Domenico; Sieri, Sabina; Tumino, Rosario; Sacerdote, Carlotta; Galasso, Rocco; Redondo, Maria-Luisa; Bonet Bonet, Catalina; Molina-Montes, Esther; Altzibar, Jone M.; Chirlaque, Maria-Dolores; Ardanaz, Eva; Bueno-de-Mesquita, H. Bas; van Duijnhoven, Franzel J. B.; Peeters, Petra H. M.; Onland-Moret, N. Charlotte; Lundin, Eva; Idahl, Annika; Khaw, Kay-Tee; Wareham, Nicholas; Allen, Naomi; Romieu, Isabelle; Fedirko, Veronika; Hainaut, Pierre; Romaguera, Dora; Norat, Teresa; Riboli, Elio; Kaaks, Rudolf

    2011-01-01

    Chronic inflammation has been hypothesized to play a role in endometrial cancer development. Tumor necrosis factor-alpha (TNF-alpha), one of the major pro-inflammatory cytokines, has also been implicated in endometrial physiology. We conducted a case-control study nested within the European prospect

  7. Tumor necrosis factor alpha gene polymorphism in multiple sclerosis and optic neuritis

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Sandberg-Wollheim, M;

    1990-01-01

    The NcoI tumor necrosis factor (TNF alpha) polymorphism was studied in relapsing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the NcoI marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were...

  8. Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways

    NARCIS (Netherlands)

    Langen, R.C.J.; Schols, A.M.W.J.; Kelders, M.C.J.M.; van der Velden, A.L.J.; Wouters, E.F.M.; Janssen, Y.M.W.

    2002-01-01

    Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways. Langen RC, Schols AM, Kelders MC, Van Der Velden JL, Wouters EF, Janssen-Heininger YM. Department of Pulmonology, Maastricht University, The Netherlands. Muscle wasting accompanies diseases that are as

  9. Effect of tumor necrosis factor-alpha infusion on the incretin effect in healthy volunteers

    DEFF Research Database (Denmark)

    Nielsen, Signe Tellerup; Lehrskov-Schmidt, Louise; Krogh-Madsen, Rikke;

    2013-01-01

    Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumor necrosis factor-alpha (TNF-α). Whereas TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce...

  10. Systemic side effects of isolated limb perfusion with tumor necrosis factor alpha

    NARCIS (Netherlands)

    Zwaveling, Jan Harm

    1997-01-01

    The main function of tumor necrosis factor alpha (TNF-a), a small polypeptide shared by all mammals, is probably protection against invading bacteria, parasites and viruses; killing of these microorganisms is facilitated in the presence of TNF-a. However, as its name suggest, TNF-a is also capable o

  11. Amrinone suppresses the synthesis of tumor necrosis factor-alpha in human mononuclear cells

    NARCIS (Netherlands)

    Endres, S; Sinha, B; Fülle, H J

    1994-01-01

    Tumor necrosis factor-alpha (TNF) exerts a wide spectrum of biological activities and contributes to the pathophysiology of septic shock. Elevated circulating levels of TNF have also been reported in patients with severe chronic heart failure. We studied the effect of amrinone, a class III cyclic nu

  12. The effect of anti-tumor necrosis factor alpha agents on postoperative anastomotic complications in Crohn's disease

    DEFF Research Database (Denmark)

    El-Hussuna, Alaa Abdul-Hussein H; Krag, Aleksander; Olaison, Gunnar

    2013-01-01

    Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications.......Patients with Crohn's disease treated with anti-tumor necrosis factor alpha agents may have an increased risk of surgical complications....

  13. Synergism between human tumor necrosis factor and human interferon-alpha: effects on cells in culture.

    Science.gov (United States)

    Orita, K; Ando, S; Kurimoto, M

    1987-08-01

    The cytostatic and cytotoxic effects of highly purified natural human tumor necrosis factor (HuTNF-alpha) and natural human interferon-alpha (HuIFN-alpha) on 23 cell lines were studied in vitro. Natural HuTNF-alpha showed cytostatic and cytotoxic effects on PC-9, KHG-2, HT-1197, KG-1 and L-929 cells, and HuIFN-alpha showed both effects on KHG-2 and Daudi cells. A mixture of HuTNF-alpha and HuIFN-alpha (1:1, by unit) showed cytostatic and cytotoxic effects on HuTNF-alpha- or HuIFN-alpha-resistant cell lines such as KB, KATO-III, HEp-2, P-4788, as well as on HuTNF-alpha- or HuIFN-alpha-susceptible cells. Thus, the combined preparation of HuTNF-alpha and HuIFN-alpha expanded the spectrum of sensitive cells. The dosage of the mixed preparation required to produce 50% inhibition of cell growth was less than 20% of that of HuTNF-alpha or HuIFN-alpha alone. These results indicate that the cytostatic and cytotoxic effects of HuTNF-alpha and HuIFN-alpha are synergistically enhanced when they are administered together.

  14. Synergism between human tumor necrosis factor and human interferon-alpha: effects on cells in culture.

    Directory of Open Access Journals (Sweden)

    Orita,Kunzo

    1987-08-01

    Full Text Available The cytostatic and cytotoxic effects of highly purified natural human tumor necrosis factor (HuTNF-alpha and natural human interferon-alpha (HuIFN-alpha on 23 cell lines were studied in vitro. Natural HuTNF-alpha showed cytostatic and cytotoxic effects on PC-9, KHG-2, HT-1197, KG-1 and L-929 cells, and HuIFN-alpha showed both effects on KHG-2 and Daudi cells. A mixture of HuTNF-alpha and HuIFN-alpha (1:1, by unit showed cytostatic and cytotoxic effects on HuTNF-alpha- or HuIFN-alpha-resistant cell lines such as KB, KATO-III, HEp-2, P-4788, as well as on HuTNF-alpha- or HuIFN-alpha-susceptible cells. Thus, the combined preparation of HuTNF-alpha and HuIFN-alpha expanded the spectrum of sensitive cells. The dosage of the mixed preparation required to produce 50% inhibition of cell growth was less than 20% of that of HuTNF-alpha or HuIFN-alpha alone. These results indicate that the cytostatic and cytotoxic effects of HuTNF-alpha and HuIFN-alpha are synergistically enhanced when they are administered together.

  15. Tumor necrosis factor-alpha modulates human in vivo lipolysis

    DEFF Research Database (Denmark)

    Plomgaard, Peter; Fischer, Christian P; Ibfelt, Tobias;

    2008-01-01

    in lipolysis, increasing circulatory free fatty acid (FFA) levels. SUBJECTS AND METHODS: Using a randomized controlled, crossover design, healthy young male individuals (n = 10) received recombinant human (rh) TNF-alpha (700 ng/m(-2).h(-1)) for 4 h, and energy metabolism was evaluated using a combination...

  16. Tumor necrosis factor-alpha induced enhancement of cryosurgery

    Science.gov (United States)

    Goel, Raghav; Paciotti, Guilio F.; Bischof, John C.

    2008-02-01

    Local recurrence of cancer after cryosurgery is related to the inability to monitor and predict destruction of cancer (temperatures > -40°C) within an iceball. We previously reported that a cytokine adjuvant TNF-α could be used to achieve complete cancer destruction at the periphery of an iceball (0 to -40°C). This study is a further development of that work in which cryosurgery was performed using cryoprobes operating at temperatures > -40°C. LNCaP Pro 5 tumor grown in a dorsal skin fold chamber (DSFC) was frozen at -6°C after TNF-α incubation for 4 or 24 hours. Tumors grown in the hind limb were frozen with a probe tip temperature of -40°C, 4 or 24 hours after systemic injection with TNF-α. Both cryosurgery alone or TNF-α treatment alone caused only a minimal damage to the tumor tissue at the conditions used in the study. The combination of TNF-α and cryosurgery produced a significant damage to the tumor tissue in both the DSFC and the hind limb model system. This augmentation in cryoinjury was found to be time-dependent with 4-hour time period between the two treatments being more effective than 24-hour. These results suggests the possibility of cryotreatment at temperatures > -40°C with the administration of TNF-α.

  17. [Neurological complications during treatment of the tumor necrosis alpha inhibitors].

    Science.gov (United States)

    Piusińska-Macoch, Renata

    2013-05-01

    Medications with TNF-alpha inhibitors family are successfully applicable in rheumatology, gastroenterology, dermatology and neurology. Still, the ongoing research on the safety assessment of their application, also due to neurological complications. The vast majority of these complications is associated with an increased risk of serious virus (Herpes simplex--JC) and bacterial (Listeria monocytogenes) neuroinfections. They can cause the occurrence of progressive multifocal leukoencephalopathy--PML with a severe clinical course and poor prognosis or herpes simplex encephalitis--HSE. Meta-analysis revealed a number of cases of PML and the HSE in the first 6 months of treatment with natalizumab, efalizumab, rituximab, abatacept and infliximab. Common complication occasionally turning on this biologics is chronic demyelinating polyneuropathy or Lewis-Sumner syndrome. Described are cases of central and peripheral demyelination typical of multiple sclerosis (MS). Are also reported cases of motor multifocal neuropathy with conduction block acute encephalithis with polyneuropathy or mononeuropathy in the form of anterior optic neuropathy Guillen-Barre' syndrome and its variant, Miller-Fisher syndrome have been confirmed as adverse events following treatment with infliximab. Also revealed several cases of myasthenia gravis after using etanercept. In the few cases of systemic lupus CNS involvement caused by treatment with TNF inhibitors, the mechanism of these disorders is still considered too vague. Due to the emerging reports on the number of neurological adverse events of TNF antagonists, significantly higher than those described in the literature, the safety of their use requires further monitoring and multicenter studies.

  18. Cytomegalovirus colitis in a patient with Behcet's disease receiving tumor necrosis factor alpha inhibitory treatment

    Institute of Scientific and Technical Information of China (English)

    Ismail Sari; Merih Birlik; Can Gonen; Server Akar; Duygu Gurel; Fatos Onen; Nurullah Akkoc

    2008-01-01

    Anti-tumor necrosis factor alpha (TNF-α) inhibitors are effective in the treatment of various inflammatory rheumatic conditions. Increased risks of serious infections are the major issues concerning the long-term safety of these agents. We present a case of a young male Behcet's patient whose disease was complicated by cytomegalovirus (CMV) colitis. Colitis started 10 d after the third Infliximab dose and responded to the cessation of TNF blocking treatment and administration of ganciclovir. Tumor necrosis factor alpha and interferon gamma act at several levels in combating viral infections.CMV infections should be kept in mind and included in the differential diagnosis of severe gastrointestinal symptoms in patients receiving anti-TNF agents.

  19. Roles of tumor necrosis factor alpha on sperm acrosin activity and acrosome reaction

    Institute of Scientific and Technical Information of China (English)

    Shu-LingBian; Guo-YiLiu; Hai-XiaWen; Shu-ZhenWang; JiangNi; WeiZhang; HuiSi

    2004-01-01

    Aim: To study the roles of tumor necrosis factor alpha (TNF-a)on the sperm acrosin activity and acrosome reaction. Methods:The sperm acrosin activity was tested by the method of BAEE/ADH Unity and the acrosome reaction by the Triple-stain technique. Results: TNF-a decreased the sperm acrosin activityand acrosome reaction (P<0.01, P<0.01, respectively);

  20. Anti-Tumor Necrosis Factor Alpha for Retinal Diseases: Current Knowledge and Future Concepts

    OpenAIRE

    Alireza Mirshahi; René Hoehn; Katrin Lorenz; Christina Kramann; Holger Baatz

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers ar...

  1. Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

    Directory of Open Access Journals (Sweden)

    Agarwal Pankaj

    2007-01-01

    Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

  2. Elevated levels of tumor necrosis factor alpha and mortality in centenarians

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Andersen-Ranberg, Karen; Hjelmborg, Jacob v B;

    2003-01-01

    BACKGROUND: Aging is accompanied by low-grade inflammation. Tumor necrosis factor (TNF) alpha initiates the cytokine cascade, and high levels are associated with dementia and atherosclerosis in persons aged 100 years. We hypothesized that TNF-alpha was also a prognostic marker for all-cause morta...... as confounders. CONCLUSION: TNF-alpha was an independent prognostic marker for mortality in persons aged 100 years, suggesting that it has specific biological effects and is a marker of frailty in the very elderly.......BACKGROUND: Aging is accompanied by low-grade inflammation. Tumor necrosis factor (TNF) alpha initiates the cytokine cascade, and high levels are associated with dementia and atherosclerosis in persons aged 100 years. We hypothesized that TNF-alpha was also a prognostic marker for all......-cause mortality in these persons. METHODS: We enrolled 126 subjects at or around the time of their 100th birthday. Plasma levels of TNF-alpha, interleukin (IL)-6, IL-8, and C-reactive protein were measured at baseline, and we determined the associations between the markers of inflammation and mortality during...

  3. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Geborek, Pierre; Svenson, Morten

    2006-01-01

    Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial...

  4. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling.

    Science.gov (United States)

    Banno, Tomohiro; Gazel, Alix; Blumenberg, Miroslav

    2004-07-30

    Identification of tumor necrosis factor-alpha (TNF alpha) as the key agent in inflammatory disorders, e.g. rheumatoid arthritis, Crohn's disease, and psoriasis, led to TNF alpha-targeting therapies, which, although avoiding many of the side-effects of previous drugs, nonetheless causes other side-effects, including secondary infections and cancer. By controlling gene expression, TNF alpha orchestrates the cutaneous responses to environmental damage and inflammation. To define TNF alpha action in epidermis, we compared the transcriptional profiles of normal human keratinocytes untreated and treated with TNF alpha for 1, 4, 24, and 48 h by using oligonucleotide microarrays. We found that TNF alpha regulates not only immune and inflammatory responses but also tissue remodeling, cell motility, cell cycle, and apoptosis. Specifically, TNF alpha regulates innate immunity and inflammation by inducing a characteristic large set of chemokines, including newly identified TNF alpha targets, that attract neutrophils, macrophages, and skin-specific memory T-cells. This implicates TNF alpha in the pathogenesis of psoriasis, fixed drug eruption, atopic and allergic contact dermatitis. TNF alpha promotes tissue repair by inducing basement membrane components and collagen-degrading proteases. Unexpectedly, TNF alpha induces actin cytoskeleton regulators and integrins, enhancing keratinocyte motility and attachment, effects not previously associated with TNF alpha. Also unanticipated was the influence of TNF alpha upon keratinocyte cell fate by regulating cell-cycle and apoptosis-associated genes. Therefore, TNF alpha initiates not only the initiation of inflammation and responses to injury, but also the subsequent epidermal repair. The results provide new insights into the harmful and beneficial TNF alpha effects and define the mechanisms and genes that achieve these outcomes, both of which are important for TNF alpha-targeted therapies.

  5. High Serum Interleukin-10 and Tumor Necrosis Factor Alpha Levels in Chronic Paracoccidioidomycosis

    Science.gov (United States)

    Fornari, M. C.; Bava, A. J.; Guereño, M. T.; Berardi, V. E.; Silaf, M. R.; Negroni, R.; Diez, R. A.

    2001-01-01

    In patients with chronic paracoccidioidomycosis (n = 10), levels of tumor necrosis factor alpha, interleukin-10, and interleukin-2 in serum, measured by enzyme-linked immunosorbent assay (in picograms per milliliter, as mean ± standard error of the mean), were higher than in normal controls (n = 8): 186 ± 40 versus 40 ± 7 (P < 0.05), 203 ± 95 versus 20 ± 8 (P = 0.001), and 96.3 ± 78.57 versus 1.19 ± 1.19 (P = 0.045), respectively. Gamma interferon and interleukin-4 levels were similar in patients and controls. PMID:11527826

  6. NO ASSOCIATION BETWEEN TUMOR NECROSIS FACTOR ALPHA AND OBSESSIVE COMPULSIVE DISORDER IN CHINESE HAN POPULATION

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    Objective To investigate association between tumor necrosis factor alpha (TNF-α) and obsessive compulsive disorder (OCD) in Chinese Han population.Methods Plasma concentrations of TNF-α were measured in 61 drug-free patients who fulfilled DSM-Ⅳ criteria for OCD and 93 healthy controls.TNF-α concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA).Two polymorphisms of TNF-α gene were investigated in the same patients and healthy controls:-308 G/A and-238 G/A.The allelic and genoty...

  7. Coupling purification and on-column PEGylation of tumor necrosis factor alpha analogue.

    Science.gov (United States)

    Milunović, Tatjana; Kunstelj, Menči; Fidler, Katarina; Anderluh, Gregor; Gaberc Porekar, Vladka

    2012-11-15

    Trends in preparation of PEGylated protein drugs strive for simple, fast, and cheap processes, resulting in well-defined homogeneous products. We investigated the on-column PEGylation of tumor necrosis factor alpha (TNF-α), where purification and conjugation were performed in one step by using immobilized metal affinity chromatography (IMAC). The same quality of the PEGylated product was obtained by the on-column approach starting from either the crude Escherichia coli protein extract or the purified protein. In comparison with the PEGylation in solution, the on-column approach resulted in more homogeneous PEGylated product. The on-column PEGylation reduces the number of production steps, costs, and preparation time.

  8. Bilateral optic neuropathy associated with the tumor necrosis factor-alpha inhibitor golimumab.

    Science.gov (United States)

    Chang, Jessica R; Miller, Neil R

    2014-12-01

    A 62-year-old man developed bilateral blurred vision associated with bilateral optic disc swelling shortly after receiving his third dose of the tumor necrosis factor-alpha (TNF-α) inhibitor golimumab, that he took for psoriatic arthritis. An extensive assessment including magnetic resonance imaging, lumbar puncture, and serologies was negative. He was treated with systemic corticosteroids and the golimumab was stopped, after which his vision improved and his disc swelling resolved. We postulate that the bilateral, simultaneous anterior optic neuropathies in this patient were due to golimumab, representing a rare but well-documented serious adverse event associated with TNF-α inhibitors.

  9. Immunological effects of a tumor necrosis factor alpha-armed oncolytic adenovirus.

    Science.gov (United States)

    Hirvinen, Mari; Rajecki, Maria; Kapanen, Mika; Parviainen, Suvi; Rouvinen-Lagerström, Noora; Diaconu, Iulia; Nokisalmi, Petri; Tenhunen, Mikko; Hemminki, Akseli; Cerullo, Vincenzo

    2015-03-01

    For long it has been recognized that tumor necrosis factor alpha (TNFa) has anticancer characteristics, and its use as a cancer therapeutic was proposed already in the 1980s. However, its systemic toxicity has limited its usability. Oncolytic viruses, selectively cancer-killing viruses, have shown great potency, and one of their most useful aspects is their ability to produce high amounts of transgene products locally, resulting in high local versus systemic concentrations. Therefore, the overall magnitude of tumor cell killing results from the combination of oncolysis, transgene-mediated direct effect such as TNFa-mediated apoptosis, and, perhaps most significantly, from activation of the host immune system against the tumor. We generated a novel chimeric oncolytic adenovirus expressing human TNFa, Ad5/3-D24-hTNFa, whose efficacy and immunogenicity were tested in vitro and in vivo. The hTNFa-expressing adenovirus showed increased cancer-eradicating potency, which was shown to be because of elevated apoptosis and necrosis rates and induction of various immune responses. Interestingly, we saw increase in immunogenic cell death markers in Ad5/3-d24-hTNFa-treated cells. Moreover, tumors treated with Ad5/3-D24-hTNFa displayed enhanced presence of OVA-specific cytotoxic T cells. We thus can conclude that tumor eradication and antitumor immune responses mediated by Ad5/3-d24-hTNFa offer a new potential drug candidate for cancer therapy.

  10. Prostacyclin analogs suppress the synthesis of tumor necrosis factor-alpha in LPS-stimulated human peripheral blood mononuclear cells

    NARCIS (Netherlands)

    Eisenhut, T; Sinha, B; Gröttrup-Wolfers, E; Semmler, J; Siess, W; Endres, S

    1993-01-01

    Recent reports have shown that prostaglandin E2 (PGE2) is able to suppress lipopolysaccharide (LPS)-stimulated production of tumor necrosis factor-alpha (TNF-alpha). In the present study we compared PGE2 with prostacyclin (PGI2) analogs in their potency to influence LPS-stimulated production of inte

  11. Effects of endotoxin and tumor necrosis factor alpha on regional brain neurotransmitters in mice.

    Science.gov (United States)

    Cho, L; Tsunoda, M; Sharma, R P

    1999-01-01

    Alterations in regional brain concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites were investigated in male BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS, 2 mg kg(-1)) or recombinant murine tumor necrosis factor alpha (TNFalpha, 0.1 mg kg(-1)) at 2, 6, 12 and 24 h after the injection. At 2 h post-injection the LPS administration resulted in hypothermia, which was not apparent at later time points. No consistent effects were observed by either LPS or TNFalpha on peripheral leukocyte counts or plasma transaminase levels. Both LPS and TNFalpha slightly elevated NE metabolism in the striatum at 2-12 h. Concentrations of DA and its metabolites were significantly elevated only in the hypothalamus following TNFalpha at 24 h. Tumor necrosis factor alpha exerted pronounced effects on 5-HT metabolism in most brain regions at 2 h. Results suggest that the effect of LPS is more complex compared with TNFalpha because of the endogenous production of other cytokines including the TNFalpha.

  12. Erythropoietin protects myocardin-expressing cardiac stem cells against cytotoxicity of tumor necrosis factor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Madonna, Rosalinda [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Shelat, Harnath; Xue, Qun; Willerson, James T. [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States); De Caterina, Raffaele [Institute of Cardiology, and Center of Excellence on Aging, ' G. d' Annunzio' University, Chieti (Italy); Geng, Yong-Jian, E-mail: yong-jian.geng@uth.tmc.edu [The Center for Cardiovascular Biology and Atherosclerosis Research, The University of Texas Health Science Center at Houston, Texas (United States); The Texas Heart Institute at St. Luke' s Episcopal Hospital, Houston, Texas (United States)

    2009-10-15

    Cardiac stem cells are vulnerable to inflammation caused by infarction or ischemic injury. The growth factor, erythropoietin (Epo), ameliorates the inflammatory response of the myocardium to ischemic injury. This study was designed to assess the role of Epo in regulation of expression and activation of the cell death-associated intracellular signaling components in cardiac myoblasts stimulated with the proinflammatory cytokine tumor necrosis factor (TNF)-{alpha}. Cardiac myoblasts isolated from canine embryonic hearts characterized by expression of myocardin A, a promyogenic transcription factor for cardiovascular muscle development were pretreated with Epo and then exposed to TNF-{alpha}. Compared to untreated cells, the Epo-treated cardiac myoblasts exhibited better morphology and viability. Immunoblotting revealed lower levels of active caspase-3 and reductions in iNOS expression and NO production in Epo-treated cells. Furthermore, Epo pretreatment reduced nuclear translocation of NF-{kappa}B and inhibited phosphorylation of inhibitor of kappa B (I{kappa}B) in TNF-{alpha}-stimulated cardiac myoblasts. Thus, Epo protects cardiac myocyte progenitors or myoblasts against the cytotoxic effects of TNF-{alpha} by inhibiting NF-{kappa}B-mediated iNOS expression and NO production and by preventing caspase-3 activation.

  13. Crocin suppresses tumor necrosis factor-alpha-induced cell death of neuronally differentiated PC-12 cells.

    Science.gov (United States)

    Soeda, S; Ochiai, T; Paopong, L; Tanaka, H; Shoyama, Y; Shimeno, H

    2001-11-01

    Crocus sativus L. is used in Chinese traditional medicine to treat some disorders of the central nervous system. Crocin is an ethanol-extractable component of Crocus sativus L.; it is reported to prevent ethanol-induced impairment of learning and memory in mice. In this study, we demonstrate that crocin suppresses the effect of tumor necrosis factor (TNF)-alpha on neuronally differentiated PC-12 cells. PC-12 cells dead from exposure to TNF-alpha show apoptotic morphological changes and DNA fragmentation. These hallmark features of cell death did not appear in cells treated in the co-presence of 10 microM crocin. Moreover, crocin suppressed the TNF-alpha-induced expression of Bcl-Xs and LICE mRNAs and simultaneously restored the cytokine-induced reduction of Bcl-X(L) mRNA expression. The modulating effects of crocin on the expression of Bcl-2 family proteins led to a marked reduction of a TNF-alpha-induced release of cytochrome c from the mitochondria. Crocin also blocked the cytochrome c-induced activation of caspase-3. To learn how crocin exhibits these anti-apoptotic actions in PC-12 cells, we tested the effect of crocin on PC-12 cell death induced by daunorubicin. We found that crocin inhibited the effect of daunorubicin as well. Our findings suggest that crocin inhibits neuronal cell death induced by both internal and external apoptotic stimuli.

  14. Production of tumor necrosis factors alpha and beta by human mononuclear leukocytes stimulated with mitogens, bacteria, and malarial parasites.

    OpenAIRE

    Ferrante, A; Staugas, R E; Rowan-Kelly, B; Bresatz, S; Kumaratilake, L M; Rzepczyk, C M; Adolf, G R

    1990-01-01

    Tumor necrosis factors alpha and beta (TNF-alpha and TNF-beta) are multifaceted polypeptide cytokines which may mediate some of the significant changes in cellular homeostasis which accompany the invasion of the mammalian host by viruses, bacteria, and parasites. Although it is well established that bacterial lipopolysaccharide is a potent inducer of TNF-alpha, there is still very little known of the types of agents which can trigger the production of TNFs in mononuclear leukocytes. Using an ...

  15. Tumor necrosis factor alpha affect hydrocortisone expression in mice adrenal cortex cells mainly through tumor necrosis factor alpha-receptor 1

    Institute of Scientific and Technical Information of China (English)

    XIA Hai-ming; FANG Yuan; HUANG Pei-lin

    2011-01-01

    Background Tumor necrosis factor alpha (TNF-α) is important in promoting relative adrenal insufficiency (RAI) due to systemic inflammatory response syndrome (SIRS).We identified the TNF-α receptor involved in the inhibition of adrenal corticotrophin (ACTH)-stimulated hydrocortisone release by studying the expression of TNF-α receptors in adrenal cortex Y1 cells and the effect of downregulating TNF receptors on ACTH-stimulated hydrocortisone release.Methods We used real-time PCR and immunocytochemistry to evaluate the expression of TNF receptors on Y1 cells.TNF-receptor 1 (TNF-R1) DNA fragments corresponding to the short hairpin RNA (shRNA)-sequences were synthesized and cloned into pcDNATM 6.2-GW/EmGFP expression vector.Knockdown efficiency of TNF-R1 expression was evaluated in miRNA transfected and mock-miRNA transfected Y1 cells by quantitative real-time PCR (Q-PCR).Hydrocortisone expression levels were determined in TNF-R1-knockdown and control Y1 cells treated with TNF-α and ACTH.Results Mouse adrenal cortex Y1 cells were positive for type I TNF-R1,but not type Ⅱ TNF-receptor (TNF-R2).Blocking TNF-R1 expression resulted in loss of TNF-α-mediated inhibition of ACTH-stimulated hydrocortisone expression,suggesting a role for the TNF-R1 related signaling pathway in ACTH-stimulated hydrocortisone synthesis.Conclusion The inhibitory effect of TNF-α on ACTH-stimulated hydrocortisone synthesis was mediated via TNF-R1 in adrenal cortex.

  16. Influence of ?S-globin haplotypes and hydroxyurea on tumor necrosis factor-alpha levels in sickle cell anemia

    Directory of Open Access Journals (Sweden)

    Marília Rocha Laurentino

    2014-04-01

    Full Text Available Background: Sickle cell anemia is a chronic inflammatory disease characterized by an increased production of proinflammatory cytokines including tumor necrosis factor-alpha. Hydroxyurea, by decreasing the polymerization of hemoglobin, reduces inflammatory states. The effect of the genetic polymorphisms of sickle cell patients on tumor necrosis factor-alpha levels remains unknown. Objective: The aim of this study was to investigate the association of tumor necrosis factor-alpha levels with β-globin haplotypes and the use of hydroxyurea. Methods: A cross-sectional study was performed of 67 patients with sickle cell anemia diagnosed at steady-state in a referral hospital in Fortaleza, Ceará, Brazil. A group of 26 healthy individuals was used as control. βS-haplotype analysis was performed by restriction fragment length polymorphism-polymerase chain reaction. The tumor necrosis factor-alpha levels were measured by the enzyme-linked immunosorbent assay test. Laboratory data (complete blood count and fetal hemoglobin and information regarding the use of hydroxyurea were obtained from medical records. Statistical analysis was performed using R software with the Kruskal-Wallis and Mann-Whitney tests. Statistical significance was established for p-values < 0.05 for all analyses. Results: The mean age of the participants was 35.48 years. Patients with sickle cell anemia had significantly higher tumor necrosis factor-alpha levels than controls (p-values < 0.0001. Tumor necrosis factor-alpha levels were lower in sickle cell anemia patients who were receiving hydroxyurea treatment than those who were not (p-value = 0.1249. Sickle cell anemia patients with Bantu/n genotype had significantly higher levels than patients with the Bantu/Benin genotype (p-value = 0.0021. Conclusion: In summary, βS-globin haplotypes, but not hydroxyurea therapy, have a role in modulating tumor necrosis factor-alpha levels in sickle cell anemia adults at steady-state. Many

  17. Use of anti tumor necrosis factor-alpha monoclonal antibody for ulcerative jejunoileitis

    Institute of Scientific and Technical Information of China (English)

    Gulseren Seven; Adel Assaad; Thomas Biehl; Richard A Kozarek

    2012-01-01

    Ulcerative jejunoileitis is an uncommon clinical syndrome consisting of abdominal pain,weight loss associated with diarrhea,and multiple inflammatory ulcerations and strictures of the small bowel.Ulcerative jejunoileitis can complicate established celiac disease or develop in patients de novo.Increased levels of tumor necrosis factor-alpha (TNF-α) in the small intestine of patients with untreated celiac disease are associated with a role in the immune pathogenesis of this disorder.No specific therapy has been shown to change the course of ulcerative jejunoileitis.We report a case of severe ulcerative jejunoileitis previously unresponsive to traditional therapies,including high dose corticosteroids and cyclosporine.The patient had a dramatic resolution of symptoms and a complete normalization of endoscopic findings after anti-TNF-α monoclonal antibody,infliximab (Remicade(R)).

  18. Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis

    Science.gov (United States)

    Noor, Zannatun; Watanabe, Koji; Abhyankar, Mayuresh M.; Burgess, Stacey L.; Buonomo, Erica L.

    2017-01-01

    ABSTRACT The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α) production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25) is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α. PMID:28246365

  19. Regulatory roles of tumor necrosis factor alpha-induced proteins (TNFAIPs) 3 and 9 in arthritis.

    Science.gov (United States)

    Matsumoto, Isao; Inoue, Asuka; Takai, Chinatsu; Umeda, Naoto; Tanaka, Yuki; Kurashima, Yuko; Sumida, Takayuki

    2014-07-01

    Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) have proved to be important in rheumatoid arthritis (RA) because the outcome of RA has greatly improved with the recent availability of biologics targeting them. It is well accepted that these cytokines are involved in the activation of the nuclear factor-κB (NF-κB) signaling pathway, but our understanding of the dependency of these pro-inflammatory cytokines and the link between them in RA is currently limited. Recently, we and others proved the importance of TNFα-induced protein (TNFAIP), due to the spontaneous development of arthritis in deficient animals that are dependent on IL-6. To date, nine TNFAIPs have been identified, and TNFAIP3 and TNFAIP9 were found to be clearly associated with mouse and human arthritis. In this review, we compare and discuss recent TNFAIP topics, especially focusing on TNFAIP3 and TNFAIP9 in autoimmune arthritis in mice and humans.

  20. Tumor Necrosis Factor-alpha- and interleukin-1-induced cellular responses: coupling proteomic and genomic information.

    Science.gov (United States)

    Ott, Lee W; Resing, Katheryn A; Sizemore, Alecia W; Heyen, Joshua W; Cocklin, Ross R; Pedrick, Nathan M; Woods, H Cary; Chen, Jake Y; Goebl, Mark G; Witzmann, Frank A; Harrington, Maureen A

    2007-06-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFalpha) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFalpha- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFalpha and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFalpha and IL-1 regulate different processes. A large-scale proteomic analysis of TNFalpha- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFalpha and IL-1. When combined with genomic studies, our results indicate that TNFalpha, but not IL-1, mediates cell cycle arrest.

  1. Dynamic equilibrium unfolding pathway of human tumor necrosis factor-alpha induced by guanidine hydrochloride.

    Science.gov (United States)

    Kim, Y R; Hahn, J S; Hong, H; Jeong, W; Song, N W; Shin, H C; Kim, D

    1999-01-11

    The dynamic equilibrium unfolding pathway of human tumor necrosis factor-alpha (TNF-alpha) during denaturation at different guanidine hydrochloride (GdnHCl) concentrations (0-4.2 M) was investigated by steady-state fluorescence spectroscopy, potassium iodide (KI) fluorescence quenching, far-UV circular dichroism (CD), picosecond time-resolved fluorescence lifetime, and anisotropy decay measurements. We utilized the intrinsic fluorescence of Trp-28 and Trp-114 to characterize the conformational changes involved in the equilibrium unfolding pathway. The detailed unfolding pathway under equilibrium conditions was discussed with respect to motional dynamics and partially folded structures. At 0-0.9 M [GdnHCl], the rotational correlation times of 22-25 ns were obtained from fluorescence anisotropy decay measurements and assigned to those of trimeric states by hydrodynamic calculation. In this range, the solvent accessibility of Trp residues increased with increasing [GdnHCl], suggesting the slight expansion of the trimeric structure. At 1.2-2.1 M [GdnHCl], the enhanced solvent accessibility and the rotational degree of freedom of Trp residues were observed, implying the loosening of the internal structure. In this [GdnHCl] region, TNF-alpha was thought to be in soluble aggregates having distinct conformational characteristics from a native (N) or fully unfolded state (U). At 4.2 M [GdnHCl], TNF-alpha unfolded to a U-state. From these results, the equilibrium unfolding pathway of TNF-alpha, trimeric and all beta-sheet protein, could not be viewed from the simple two state model (N-->U).

  2. Tumor Necrosis Factor-alpha Stimulates the Overproduction of Intestinal Apolipoprotein B48-containing Very Low Density Lipoproproteins

    Science.gov (United States)

    Tumor necrosis factor-alpha(a)(TNFa), a proinflammatory cytokine, is involved in obesity-associated pathologies including type 2 diabetes and atherosclerosis. TNFa enhanced postprandial apoB48-VLDL1 overproduction by about 89% compared with the control after 90 min olive oil loading; TNFa did not si...

  3. Tumor Necrosis Factor-alpha Inhibitor Etanercept Does Not Alter Methotrexate-induced Gastrointestinal Mucositis in Rats

    NARCIS (Netherlands)

    Kuiken, Nicoline S S; Rings, Edmond H H M; Alffenaar, Jan-Willem C; Havinga, Rick; Jurdzinski, Angelika; Groen, Albert K; Tissing, Wim J E

    2016-01-01

    OBJECTIVES: Gastrointestinal (GI) mucositis is a severe side effect of chemotherapy and radiotherapy. Pro-inflammatory cytokines are thought to play an important role in the pathophysiology of GI mucositis. We aimed to determine the effect of the Tumor Necrosis Factor-alpha (TNF-α) inhibitor Etanerc

  4. Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

    Science.gov (United States)

    DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

    2016-01-01

    Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

  5. Tumor necrosis factor alpha of teleosts: in silico characterization and homology modeling

    Directory of Open Access Journals (Sweden)

    Tran Ngoc Tuan

    2016-10-01

    Full Text Available Tumor necrosis factor alpha (TNF- is known to be crucial in many biological activities of organisms. In this study, physicochemical properties and modeling of TNF- protein of fish was analyzed using in silico approach. TNF- proteins selected from fish species, including grass carp (Ctenopharyngodon idella, zebra fish (Danio rerio, Nile tilapia (Oreochromis niloticus, goldfish (Carassius auratus, and rainbow trout (Oncorhynchus mykiss were used in this study. Physicochemical characteristics with molecular weight, theoretical isoelectric point, extinction coefficient, aliphatic index, instability index, total number of negatively charged residues and positively charged residues, and grand average of hydropathicity were computed. All proteins were classified as transmembrane proteins. The “transmembrane region” and “TNF” domain were identified from protein sequences. The function prediction of proteins was also performed. Alpha helices and random coils were dominating in the secondary structure of the proteins. Three-dimensional structures were predicted and verified as good structures for the investigation of TNF- of fish by online server validation.

  6. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists.

    Science.gov (United States)

    Bendtzen, Klaus

    2013-04-01

    With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies.

  7. Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions

    DEFF Research Database (Denmark)

    Schuchmann, M; Hess, S; Bufler, P;

    1995-01-01

    interaction with the human p55TNFR. This was demonstrated in NIH 3T3 cells transfected with the human p55TNFR, where cytotoxicity is mediated exclusively by the transfected receptor. Although the p55ATNFR had virtually identical affinities for TNF and LT alpha, as defined by Scatchard analysis......Tumor necrosis factor (TNF) and lymphotoxin alpha (LT alpha) are closely related cytokines which bind with nearly identical affinities to the same pair of cell surface receptors, p55 and p75TNFR. Therefore it is assumed that TNF and LT alpha are redundant cytokines. This study, however...

  8. Detection of circulant tumor necrosis factor-alpha , soluble tumor necrosis factor p75 and interferon-gamma in Brazilian patients with dengue fever and dengue hemorrhagic fever

    Directory of Open Access Journals (Sweden)

    Elzinandes LA Braga

    2001-02-01

    Full Text Available Pro-inflammatory cytokines are believed to play an important role in the pathogenesis of dengue infection. This study reports cytokine levels in a total of 54 patients examined in Recife, State of Pernambuco, Brazil. Five out of eight patients who had hemorrhagic manifestations presented tumor necrosis factor-alpha (TNF-alpha levels in sera which were statistically higher than those recorded for controls. In contrast, only one out of 16 patients with mild manifestations had elevated TNF-alpha levels. The levels of interleukin-6 (IL, IL-1beta tested in 24 samples and IL-12 in 30 samples were not significantly increased. Interferon-g was present in 10 out of 30 patients with dengue. The data support the concept that the increased level of TNF-alpha is related to the severity of the disease. Soluble TNF receptor p75 was found in most patients but it is unlikely to be related to severity since it was found with an equivalent frequency and levels in 15 patients with dengue fever and another 15 with dengue hemorrhagic fever.

  9. Tumor Necrosis Factor alpha (TNF{alpha}) regulates CD40 expression through SMAR1 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Kamini; Sinha, Surajit; Malonia, Sunil Kumar; Chattopadhyay, Samit, E-mail: samit@nccs.res.in

    2010-01-08

    CD40 plays an important role in mediating inflammatory response and is mainly induced by JAK/STAT phosphorylation cascade. TNF{alpha} is the key cytokine that activates CD40 during inflammation and tumorigenesis. We have earlier shown that SMAR1 can repress the transcription of Cyclin D1 promoter by forming a HDAC1 dependent repressor complex. In this study, we show that SMAR1 regulates the transcription of NF-{kappa}B target gene CD40. SMAR1 recruits HDAC1 and forms a repressor complex on CD40 promoter and keeps its basal transcription in check. Further, we show that TNF{alpha} stimulation induces SMAR1 phosphorylation at Ser-347 and promotes its cytoplasmic translocation, thus releasing its negative effect. Concomitantly, TNF{alpha} induced phosphorylation of STAT1 at Tyr-701 by JAK1 facilitates its nuclear translocation and activation of CD40 through p300 recruitment and core Histone-3 acetylation. Thus, TNF{alpha} mediated regulation of CD40 expression occurs by dual phosphorylation of SMAR1 and STAT1.

  10. Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

    DEFF Research Database (Denmark)

    Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj

    2003-01-01

    -alpha was smaller (PTNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. CONCLUSIONS: These results support the concept that TNF-alpha could play a role......BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow...

  11. Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Dominguez, Helena; Storgaard, Heidi; Rask-Madsen, Christian

    2005-01-01

    OBJECTIVE: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic...... insulin resistance. METHOD AND RESULTS: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions...

  12. Plasma Levels of Tumor Necrosis Factor-Alpha and Interleukin-6 in Obsessive Compulsive Disorder

    Directory of Open Access Journals (Sweden)

    N. Konuk

    2007-01-01

    Full Text Available Aim. Recent research implicated place of an immune mechanism in the pathophysiology of obsessive-compulsive disorder (OCD. Despite increasing evidence involvement of cytokine release in OCD, results of the studies are inconsistent. The aim of this study was to evaluate the plasma levels of the cytokines; tumor necrosis factor-alpha (TNF-α and interleukin-6 (IL-6 in OCD patients. Methods. Plasma concentrations of TNF-α and IL-6 were measured in 31 drug-free outpatients with OCD, and 31-year age and sex-matched healthy controls. TNF-α and IL-6 concentrations in blood were determined by enzyme-linked immunosorbent assay (ELISA. Results. Both TNF-α and IL-6 levels showed statistically significant increases in OCD patients compared to controls (P<.000, P<.001, resp.. In addition, the age of onset was negatively correlated with TNF-α level (r=−.402, P=.025 and duration of illness was weakly correlated with IL-6 levels (r:.357; P:.048 in patients group. Conclusion. OCD patients showed increases in TNF-α and IL-6 levels compared to the healthy controls. This study provides evidence for alterations in the proinflamatory cytokines which suggest the involvement of the immune system in the pathophysiology of OCD.

  13. Anti-Tumor Necrosis Factor Alpha for Retinal Diseases: Current Knowledge and Future Concepts

    Directory of Open Access Journals (Sweden)

    Alireza Mirshahi

    2012-01-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

  14. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts.

    Science.gov (United States)

    Mirshahi, Alireza; Hoehn, René; Lorenz, Katrin; Kramann, Christina; Baatz, Holger

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory cytokine produced by macrophages and T-cells. It plays an important role both in inflammation and apoptosis. In the eye, TNF-α appears to have a role in the pathogenesis of inflammatory, edematous, neovascular and neurodegenerative disorders. Several TNF-blocking drugs have been developed and approved, and are in clinical use for inflammatory diseases such as rheumatoid arthritis, psoriasis and ankylosing spondylitis. TNF-α blockers are widely used in ophthalmology as an off-label alternative to "traditional" immunosuppressive and immune-modulatory treatments in noninfectious uveitis. Preliminary studies suggest a positive effect of intravenously administered TNF-α blockers, mainly infliximab, for treating refractory diabetic macular edema and neovascular age-related macular degeneration. Unfortunately, much of the current data raises considerable safety concerns for intravitreal use of TNF-α inhibitors, in particular, intraocular inflammatory responses have been reported after intravitreal injection of infliximab. Results of dose-finding studies and humanized antibody or antibody fragments (e.g. adalimumab) are anticipated in the coming years; these will shed light on potential benefits and risks of local and systemic TNF-α blockers used for treatment of diseases of the retina and choroid.

  15. Chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab in psoriasis

    Directory of Open Access Journals (Sweden)

    Sridhar J

    2006-01-01

    Full Text Available Background: Insights into the pathogenesis of psoriasis have provided opportunities to target key steps in the disease process. Tumor necrosis factor-alpha (TNF-a being crucial to the pathogenesis of psoriasis, monoclonal antibodies against this cytokine have proved useful in its treatment. Aim: To study the efficacy of chimeric monoclonal antibody to TNF-a (infliximab in Indian patients with recalcitrant psoriasis vulgaris. Materials and Methods: Three patients with recalcitrant psoriasis vulgaris were studied. Baseline haemogram, biochemical parameters, chest radiograph and Mantoux skin test were performed. A loading dose regimen of 5 mg/kg infliximab was administered at weeks 0, 2 and 6. PASI assessment, adverse drug event monitoring and laboratory assessments were carried out at 2-week intervals until week 10. Patients were followed up until week 22 for relapse. Results: Infliximab was well tolerated. The mean PASI was 25.4 at presentation and declined to 5.5 at 10 weeks. PASI 75 was attained at a mean of 9.6 weeks. Relapse occurred at a mean of 18.6 weeks after the first infusion. Conclusions: This study on Indian patients brings out the importance of cytokine-based therapies in psoriasis. Indigenous production could make these therapies a viable therapeutic option for psoriasis patients in the near future.

  16. Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons.

    Science.gov (United States)

    McGuire, S O; Ling, Z D; Lipton, J W; Sortwell, C E; Collier, T J; Carvey, P M

    2001-06-01

    Levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) are increased in postmortem brain and cerebral spinal fluid from patients with Parkinson's disease (PD). This observation provides a basis for associating TNFalpha with neurodegeneration, but a specific toxicity in dopamine (DA) neurons has not been firmly established. Therefore, we investigated TNFalpha-induced toxicity in DA neurons by utilizing primary cultures of embryonic rat mesencephalon. Exposure to TNFalpha resulted in a dose-dependent decrease in DA neurons as evidenced by decreased numbers of tyrosine hydroxylase-immunoreactive (THir) cells. TNFalpha toxicity was selective for DA neurons in that neither glial cell counts nor the total number of neurons was decreased and no general cytotoxicity was evidenced by lactate dehydrogenase assay. Many of the cells which remained immunoreactive for TH had shrunken and rounded cell bodies with broken, blunted, or absent processes. However, TNFalpha-treated cultures also contained some THir cells which appeared to be undamaged and possibly resistant to TNFalpha-induced toxicity. Additionally, immunocytochemistry revealed basal expression of TNFalpha receptor 1 (p55, R1) and TNFalpha receptor 2 (p75, R2) on all cells within the mesencephalic cultures to some degree, even though only DA neurons were affected by TNFalpha treatment. These data strongly suggest that TNFalpha mediates cell death in a sensitive population of DA neurons and support the potential involvement of proinflammatory cytokines in the degeneration of DA neurons in PD.

  17. Tumor Necrosis Factor-Alpha in Peripical Tissue Exudates of Teeth with Apical Periodontitis

    Directory of Open Access Journals (Sweden)

    Sonja Pezelj-Ribaric

    2007-01-01

    Full Text Available Aim. The aim of this study was to determine tumor necrosis factor-alpha (TNF-α levels in periapical exudates and to evaluate their relationship with radiological findings. Methodology. Periapical exudates were collected from root canals of 60 single-rooted teeth using absorbent paper points. TNF-α levels were determined by enzyme-linked immunosorbent assays. The samples were divided into three groups according to the periapical radiolucent area. Results. Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentrations in control group (40, 57±28, 15 pg/mL and group with larger radiolucent areas (2365, 79±582, 95 pg/mL, as well as between control and canals with small radiolucent areas (507, 66±278, 97 (P<.05. Conclusions. The levels of TNF-α increase significantly in teeth with periapical pathosis, from smaller to bigger lesions. This research and its results have shown that objective analysis of the TNF-α levels enables establishment of a relationship between different concentrations of TNF-α and different radiological changes.

  18. Expression of tumor necrosis factor-alpha converting enzyme in liver regeneration after partial hepatectomy

    Institute of Scientific and Technical Information of China (English)

    Xian-Ming Lin; Ying-Bin Liu; Fan Zhou; Yu-Lian Wu; Li Chen; He-Qing Fang

    2008-01-01

    AIM:To study the expression of tumor necrosis factor-alpha converting enzyme (TACE) and evaluate its significance in liver regeneration after partial hepatectomy in vivo.METHODS:Male SD rats underwent 70% partial hepatec-tomy.The remaining liver and spleen tissue samples were collected at indicated time points after hepatectomy.TACE expression was investigated by Western blotting,immunohistochemistry,and serial section immunostaining.RESULTS:Expression of TACE in liver and spleen tissues after partial hepatectomy was a time-dependent alteration,reaching a maximal level between 24 and 48 h and remaining elevated for more than 168 h.TACE protein was localized to mononuclear cells (MNC),which infiltrated the liver from the spleen after hepatectomy.The kinetics of TACE expression was in accordance with the number of TACE-staining MNCs and synchronized with those of transforming growth factor-α(TGFα).In addition,TACE-staining MNC partially overlapped with CD3+ T lymphocytes.CONCLUSION:TACE may be involved in liver regenera-tion by pathway mediated with TGFα-EGFR in the cell-cycle progressive phase in vivo.TACE production and effect by paracrine may be a pathway of involvement in liver regeneration for the activated CD3+ T lymphocytes.

  19. Tumor necrosis factor-alpha inhibits pre-osteoblast differentiation through its type-1 receptor.

    Science.gov (United States)

    Abbas, Sabiha; Zhang, Yan-Hong; Clohisy, John C; Abu-Amer, Yousef

    2003-04-01

    Tumor necrosis factor-alpha (TNF) is a pro-inflammatory cytokine with a profound role in many skeletal diseases. The cytokine has been described as a mediator of bone loss in osteolysis and other inflammatory bone diseases. In addition to its known bone resorptive action, TNF reduces bone formation by inhibiting osteoblast differentiation. Using primary and transformed osteoblastic cells, we first document that TNF inhibits expression of alkaline phosphatase and matrix deposition, both considered markers of osteoblast differentiation. The effects are dose- and time-dependent. Core-binding factor A1 (cbfa1) is a transcription factor critical for osteoblast differentiation, and we show here that it is activated by the osteoblast differentiation agent, beta-glycerophosphate. Therefore, we investigated whether the inhibitory effects of TNF were associated with altered activity of this transcription factor. Using retardation assays, we show that TNF significantly inhibits cbfal activation by beta-glycerophosphate, manifested by reduced DNA-binding activity. Next, we turned to determine the signaling pathway by which TNF inhibits osteoblast differentiation. Utilizing animals lacking individual TNF receptors, we document that TNFr1 is required for transmitting the cytokine's inhibitory effect. In the absence of this receptor, TNF failed to impact all osteoblast differentiation markers tested. In summary, TNF blocks expression of osteoblast differentiation markers and inhibits beta-glycerophosphate-induced activation of the osteoblast differentiation factor cbfa1. Importantly, these effects are mediated via a mechanism requiring the TNF type-1 receptor.

  20. Mutational Analysis of Region-cytotoxicity Relationship in Human Transmembrane Tumor Necrosis Factor-alpha

    Institute of Scientific and Technical Information of China (English)

    ZHENGFang; GONGFeili; LIZhuoya; JIANGXiaodan; XIONGPing; FENGWei; XUYong

    2002-01-01

    Objective:To determine the region of human transmembrane tumor necrosis factor-alpha (TM-TNFa), essential for cytotoxic activity a-gainst human breast cancer cell line MCF-7. Methods:Single amino-acid-substituted TM-TNFα mutant proteins (muteins) were produced by in vitro transcription linked translation techniques. The cDNA of TM-TNFα was site-directed mutagenized by recombinant PCR. Results:13 single amino-acid substituted TM-TNFα muteins were generated and assayed for cytotoxic activity. The cytotoxic activities of TM-TNFα muteins, eg, TM-TNFα-71/Lys, -28/Phe and 117/Leu were significantly decreased (P<0.01) compared to that of parent TM-TNFα, 143/Tyr decreased 4-folds, and-17/Thr,-39/Ser,ll9/His,35/Gly,95/Cys and 147/Phe decreased 1.5-2.5-folds, respectively. However, the cytotoxic activities of TM-TNFα-8/Arg, 31/Gly and 87/Phe showed no significant change. Conclusion:These results indicate that the regions associated with cytotoxic-activity of TM-TNFα are different with that of secretory TNF-lpha (S-TNFα). The inner cell region and transmembrane region of TM-TNFα are related to the cytotoxic activity of TM-TNFα.

  1. Dissociative symptoms reflect levels of tumor necrosis factor alpha in patients with unipolar depression

    Directory of Open Access Journals (Sweden)

    Bizik G

    2014-04-01

    Full Text Available Gustav Bizik,1 Petr Bob,1 Jiri Raboch,1 Josef Pavlat,1 Jana Uhrova,2 Hana Benakova,2 Tomas Zima2 1Center for Neuropsychiatric Research of Traumatic Stress, Department of Psychiatry and UHSL, 2Department of Clinical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic Abstract: Recent evidence indicates that the nature of interactions between the nervous system and immune system is important in the pathogenesis of depression. Specifically, alterations in pro-inflammatory cytokines have been related to the development of several psychological and neurobiological manifestations of depressive disorder, as well as to stress exposure. A number of findings point to tumor necrosis factor alpha (TNF-α as one of the central factors in these processes. Accordingly, in the present study, we test the hypothesis that specific influences of chronic stressors related to traumatic stress and dissociation are related to alterations in TNF-α levels. We performed psychometric measurement of depression (Beck Depression Inventory [BDI]-II, traumatic stress symptoms (Trauma Symptom Checklist [TSC]-40, and psychological and somatoform dissociation (Dissociative Experiences Scale [DES] and Somatoform Dissociation Questionnaire [SDQ]-20, respectively, and immunochemical measure of serum TNF-α in 66 inpatients with unipolar depression (mean age 43.1 ± 7.3 years. The results show that TNF-α is significantly related to DES (Spearman R=−0.42, P<0.01, SDQ-20 (Spearman R=−0.38, P<0.01, and TSC-40 (Spearman R=−0.41, P<0.01, but not to BDI-II. Results of the present study suggest that TNF-α levels are related to dissociative symptoms and stress exposure in depressed patients. Keywords: depression, dissociation, TNF-alpha, traumatic stress

  2. Tumor necrosis factor-alpha and interleukin-6 in early-onset neonatal sepsis

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    Prambudi Rukmono

    2016-05-01

    Full Text Available Background Neonatal sepsis remains a major cause of mortality and morbidity in newborns. Early-onset neonatal sepsis occurs in infants under the age of 72 hours, while late-onset neonatal sepsis occurs in infants over the age of 72 hours and may be due to nosocomial infection. Diagnosing neonatal sepsis is a challenge, as its clinical symptoms are not clear. Corroborating tests include routine blood, C-reactive protein (CRP, serology, tumor necrosis factor-alpha (TNF-α, and interleukin-6 (IL-6 examinations.Objective To compare the TNF-α and IL-6 levels in patients with proven and unproven early-onset neonatal sepsis (EONSMethods This case-control study was done in the Perinatology Unit, Abdul Moeloek Hospital, Lampung. Subjects were under the age of 72 hours with risk factors and clinical symptoms of sepsis. They underwent routine blood tests and blood cultures. Infants with positive cultures were considered to have proven sepsis (26 subjects and infants with negative blood cultures were considered to have unproven sepsis (26 subjects. All subjects underwent serological examinations of TNF-α and IL-6.Results There were no differences in the basic characteristics of subjects between the two groups. Levels of TNF-α in the sepsis group were significantly higher than in the unproven group [(28.30 vs. 10.96 pg/mL, respectively (P=0.001]. Furthermore, Il-6 was significantly higher in the proven sepsis group than in the unproven sepsis group [(28.3 vs. 9.69 pg/mL, respectively (P=0.006].Conclusion Levels of TNF-alpha and IL-6 are significantly higher in infants with proven than unproven early-onset neonatal sepsis.

  3. High circulating levels of tumor necrosis factor-alpha in centenarians are not associated with increased production in T lymphocytes

    DEFF Research Database (Denmark)

    Sandmand, Marie; Bruunsgaard, Helle; Kemp, Kåre

    2003-01-01

    and mortality in elderly humans. However, the cellular source and mechanisms for the increased circulating TNF-alpha levels are unknown. OBJECTIVE: The aim of the present study was to investigate if high plasma levels of TNF-alpha are associated with increased production of TNF-alpha by T lymphocytes in elderly...... humans. METHODS: TNF-alpha production by CD4+ and CD8+ T lymphocytes was measured by flow cytometry following stimulation with phorbol 12-myristate 13-acetate and ionomycin in 28 young controls, 14, 81-year-olds and 25 centenarians. RESULTS: Plasma levels of TNF-alpha increased with increasing age......BACKGROUND: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-alpha are strongly associated with morbidity...

  4. Suppressor of cytokine signalling-3 inhibits Tumor necrosis factor-alpha induced apoptosis and signalling in beta cells

    DEFF Research Database (Denmark)

    Bruun, Christine; Heding, Peter E; Rønn, Sif G

    2009-01-01

    Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction of the pancr......Tumor necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine involved in the pathogenesis of several diseases including type 1 diabetes mellitus (T1DM). TNFalpha in combination with interleukin-1-beta (IL-1beta) and/or interferon-gamma (IFNgamma) induces specific destruction...... in INSr3#2 cells and in primary rat islets. Furthermore, SOCS-3 repressed TNFalpha-induced degradation of IkappaB, NFkappaB DNA binding and transcription of the NFkappaB-dependent MnSOD promoter. Finally, expression of Socs-3 mRNA was induced by TNFalpha in rat islets in a transient manner with maximum...

  5. Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

    Science.gov (United States)

    Lei, Xu-Dan; Sun, Yan; Cai, Shi-Jiao; Fang, Yang-Wu; Cui, Jian-Lin; Li, Yu-Hao

    2016-01-01

    AIM To investigate the role of tumor necrosis factor-alpha (TNF-α) in zebrafish retinal development and myelination. METHODS Morpholino oligonucleotides (MO), which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one- to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in situ hybridization using a hepatocyte-specific mRNA probe ceruloplasmin (cp), and co-injection of TNF-α MO and TNF-α mRNA. An atonal homolog 7 (atoh7) mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zpr1, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein (mbp) was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-α morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization (hpf). mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post-fertilization (dpf) as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION TNF-α is not an essential regulator for retinal neurogenesis and optic myelination. PMID:27366683

  6. TUMOR NECROSIS FACTOR-ALPHA POLYMORPHISM AND SECRETION IN MYASTHENIA GRAVIS

    Institute of Scientific and Technical Information of China (English)

    Yu-zhou Guan; Li-ying Cui; Yan-feng Li; Jun-bao Zhang

    2005-01-01

    Objective To analyze the relationship between tumor necrosis factor-alpha (TNFo) gene promoter -308 polymorphism and myasthenia gravis (MG) in Chinese and analyze secretion of TNFo in peripheral blood mononuclear cells (PBMC) in MG patients.Methods A biallelic polymorphism at position -308 in the promoter of TNFα gene was screened by PCR amplification and NcoI recognition site. One hundred and twenty-three MG cases and 115 healthy controls were included in this study. MG patients were classified to different groups according to clinical type, age at onset, and sex respectively. PBMC were isolated from 20 patients and 20 healthy controls, and then cultured in the presence or absence of phytohemagglutinin (PHA) and acetycholine receptors (AchR). The supernatants were harvested after incubation and stored until TNFαwas assayed by enzyme-linked immunosorbent assay.Results The frequency of TNFα-308 allele 2 (A) was found significantly increase in MG patients and showed a trend especially in late onset (≥ 40 years) and male patients (P < 0.05). The allele A had no relationship with thymic pathogenesis in MG patients. But frequency of allele A was significantly higher in general type than in ocular type (P < 0.05). MG patients had a higher inducible level of TNFα by PHA and AchR, and could be down regulated after treatment.Conclusion Polymorphism in TNFα gene promoter -308 is associated with onset of MG. The microsatellite allele TNFα2 confer risk for the development of MG in Chinese patients. MG patients have a higher inducible level of TNFα.

  7. Transfection of influenza A virus nuclear export protein induces the expression of tumor necrosis factor alpha.

    Science.gov (United States)

    Lara-Sampablo, Alejandra; Flores-Alonso, Juan Carlos; De Jesús-Ortega, Nereyda; Santos-López, Gerardo; Vallejo-Ruiz, Verónica; Rosas-Murrieta, Nora; Reyes-Carmona, Sandra; Herrera-Camacho, Irma; Reyes-Leyva, Julio

    2014-06-24

    Influenza A virus genomic segments eight codes for non-structural 1 (NS1) protein that is involved in evasion of innate antiviral response, and nuclear export protein (NEP) that participates in the export of viral ribonucleoprotein (RNP) complexes, transcription and replication. Tumor necrosis factor alpha (TNF-α) is highly expressed during influenza virus infections and is considered an anti-infective cytokine. NS1 and NEP proteins were overexpressed and their role on TNF-α expression was evaluated. Both TNF-α mRNA and protein increased in cells transfected with NEP but not with NS1. We further investigate if NS1 or NEP regulates the activity of TNF-α promoter. In the presence of NEP the activity of TNF-α promoter increased significantly compared with the control (83.5±2.9 vs. 30.9±2.8, respectively; p=0.001). This effect decreased 15-fold when the TNF-α promoter distal region was deleted, suggesting the involvement of mitogen-activated protein kinases (MAPK) and NF-kB response elements. This was corroborated by testing the effect produced on TNF-α promoter by the treatment with Raf/MEK/ERK (U0126), NF-kB (Bay-11-7082) and PI3K (Ly294-002) cell signaling inhibitors. Treatment with U0126 and Bay-117082 reduced the activity of TNF-α promoter mediated by NEP (41.5±3.2, 70% inhibition; and 80.6±7.4, 35% inhibition, respectively) compared to mock-treated control. The results suggest a new role for NEP protein that participates in the transcriptional regulation of human TNF-α expression.

  8. Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

    Science.gov (United States)

    Brock, C; Brock, B; Aziz, Q; Møller, H J; Pfeiffer Jensen, M; Drewes, A M; Farmer, A D

    2016-12-12

    The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

  9. Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Pedersen, SB;

    2006-01-01

    Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients...

  10. Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice

    DEFF Research Database (Denmark)

    Clausen, Bettina Hjelm; Lambertsen, Kate Lykke; Babcock, Alicia

    2008-01-01

    BACKGROUND: Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We inv...

  11. Differential expression of cyclooxygenase-2 and its regulation by tumor necrosis factor-alpha in normal and malignant prostate cells.

    Science.gov (United States)

    Subbarayan, V; Sabichi, A L; Llansa, N; Lippman, S M; Menter, D G

    2001-03-15

    Cyclooxygenase (COX)-2 expression is elevated in some malignancies; however, information is scarce regarding COX-2 contributions to the development of prostate cancer and its regulation by inflammatory cytokines. The present study compared and contrasted the expression levels and subcellular distribution patterns of COX-1 and COX-2 in normal prostate [prostate epithelial cell (PrEC), prostate smooth muscle (PrSM), and prostate stromal (PrSt)] primary cell cultures and prostatic carcinoma cell lines (PC-3, LNCaP, and DU145). The basal COX-2 mRNA and protein levels were high in normal PrEC and low in tumor cells, unlike many other normal cells and tumor cells. Because COX-2 levels were low in prostate smooth muscle cells, prostate stromal cells, and tumor cells, we also examined whether COX-1 and COX-2 gene expression was elevated in response to tumor necrosis factor-alpha (TNF-alpha), a strong inducer of COX-2 expression. Northern blot analysis and reverse transcription-PCR demonstrated different patterns and kinetics of expression for COX-1 and COX-2 among normal cells and tumor cells in response to TNF-alpha. In particular, COX-2 protein levels increased, and the subcellular distribution formed a distinct perinuclear ring in the normal cells at 4 h after TNF-alpha exposure. The COX-2 protein levels also increased in cancer cells, but the subcellular distribution was less organized; COX-2 protein appeared diffuse in some cells and accumulated as focal deposits in the cytoplasm of other cells. TNF-alpha induction of COX-2 and prostaglandin E2 correlated inversely with induction of apoptosis. We conclude that COX-2 expression may be important to PrEC cell function. Although it is low in stromal and tumor cells, COX-2 expression is induced by TNF-alpha in these cells, and this responsiveness may play an important role in prostate cancer progression.

  12. Three polymorphisms of tumor necrosis factor-alpha and hepatitis B virus related hepatocellular carcinoma

    Science.gov (United States)

    Xiao, Qi; Fu, BiQi; Chen, Ping; Liu, Zhong Zhong; Wang, Wei; Ye, QiFa

    2016-01-01

    Abstract Background: To assess the association between tumor necrosis factor-alpha (TNF-α) G308A, G238A and C863T polymorphisms and hepatitis B virus related hepatocellular carcinoma (HBV-HCC) susceptibility. Methods: We interrogated the databases of Pubmed, Sciencedirect and Viley online library up to March 8, 2016. Odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) were calculated in a fixed-effects model or a random-effects model when appropriate. Results: In total, 12 case–control studies which containing 1580 HBV-HCC cases, 2033 HBV carrier controls, 395 HBV spontaneously recovered (SR) controls and 1116 healthy controls were included. Compared with GG genotype, the genotypes GA/AA of G308A were associated with a significantly increased HBV-HCC risk when the controls were all healthy individuals (AA vs. GG, OR 2.483, 95%CI 1.243 to 4.959; GA vs. GG, OR 1.383, 95%CI 1.028 to 1.860; GA/AA vs. GG, OR 1.381, 95%CI 1.048 to 1.820). Meanwhile, only the AA vs. GG model of G238A and HBV-HCC showed a statistic significance when the controls were healthy individuals (OR 4.776, 95%CI 1.280 to 17.819). CT genotype of TNF-α C863T could increase HBV-HCC risk whenever the controls were healthy individuals, HBV carriers or HBV recovers. Conclusion: This meta-analysis shows that AA genotype in TNF-α G308A and TNF-α G238A and CT genotype in TNF-α C863T may increase HBV-HCC risk. Therefore, HBV infection seemed to be a more important factor for tumorigenesis of HCC than genetic predisposition in G308A of TNF-α, and interaction between TNF-α C863T polymorphisms and HBV infection might be associated with increased HCC risk. PMID:27977601

  13. The clinical significance of tumor necrosis factor-alpha plasma level in patients having chronic lymphocytic leukemia.

    Science.gov (United States)

    Ferrajoli, Alessandra; Keating, Michael J; Manshouri, Taghi; Giles, Francis J; Dey, Amanda; Estrov, Zeev; Koller, Charles A; Kurzrock, Razelle; Thomas, Deborah A; Faderl, Stefan; Lerner, Susan; O'Brien, Susan; Albitar, Maher

    2002-08-15

    Tumor necrosis factor-alpha (TNF-alpha), a cytokine possessing pleiotropic biological activities, is produced by leukemic lymphocytes in patients with chronic lymphocytic leukemia (CLL) and acts as an autocrine and paracrine growth factor in this disease. In this study, TNF-alpha levels were determined in 150 patients with CLL and correlated with disease characteristics, prognostic factors, and survival. The mean TNF-alpha plasma concentration in the patients with CLL was significantly higher than in the healthy control population (16.4 versus 8.7 pg/mL; P <.0001). Patients having an elevated TNF-alpha level had more advanced Rai and Binet stage disease, higher serum beta(2)-microglobulin (beta(2)M) levels, a greater percentage of cells expressing CD38, and lower hemoglobin and platelet levels. Patients having chromosomal abnormalities such as 11q deletion, trisomy 12, and chromosome 17 aberrations had a higher mean TNF-alpha level (27.5 pg/mL) than patients having a diploid karyotype or other miscellaneous cytogenetic abnormalities (14.2 pg/mL; P <.001). The TNF-alpha level was a predictor of survival when the Cox proportional hazards model was used with TNF-alpha entered as a continuous variable (P =.0001). Also, patients having a TNF-alpha level above the mean value of 14 pg/mL had significantly shorter survival duration (P =.00001). The TNF-alpha level remained predictive of survival in Cox multivariate analysis independent of Rai staging and beta(2)M, hemoglobin, prior therapy, white cell count, and platelet level (P =.005). We conclude that the TNF-alpha level serves as a prognostic factor in patients with CLL and that inhibition of TNF-alpha in these patients could have therapeutic importance.

  14. A Pilot Study of the Association of Tumor Necrosis Factor Alpha Polymorphisms with Psoriatic Arthritis in the Romanian Population

    Directory of Open Access Journals (Sweden)

    Olivia M. Popa

    2011-08-01

    Full Text Available Tumor necrosis factor alpha (TNF-alpha is an important pro-inflammatory cytokine implicated in the pathogenesis of psoriatic arthritis. We have performed a case-control association study of three TNF-alpha gene polymorphisms in a group of Romanian psoriatic arthritis patients versus ethnically matched controls. A second group of patients with undifferentiated spondyloarthritis was used in order to look for similarities in the genetic background of the two rheumatic disorders. The −857C/T polymorphism was associated with susceptibility to psoriatic arthritis in our population at the individual level (p = 0.03, OR 1.65, 95% CI 1.05–2.57 and in combined haplotypes with the −238G/A and −308G/A SNPs. Regarding the investigated polymorphisms and derived haplotypes, no potential association was found with the susceptibility to undifferentiated spondyloarthritis in Romanian patients.

  15. Association study of the interleukin-1 gene complex and tumor necrosis factor alpha gene with suicide attempts.

    Science.gov (United States)

    Sáiz, Pilar A; García-Portilla, Paz; Paredes, Begoña; Arango, Celso; Morales, Blanca; Alvarez, Victoria; Coto, Eliécer; Bascarán, María-Teresa; Bousoño, Manuel; Bobes, Julio

    2008-06-01

    To investigate the association between four functional polymorphisms in interleukin-1 (IL-1) [IL-1 alpha -889 C/T, IL-1 beta +3953 C/T, IL-1RA (86 bp)n] and tumor necrosis factor alpha (TNFalpha) (-308A/G) genes and suicide attempts. Distribution of the aforesaid polymorphisms was analyzed in 193 suicide attempters compared with 420 unrelated healthy controls from Asturias (Northern Spain). Genotypes were determined using standard methods. No significant differences were found in genotype or in allelic distribution of IL-1 alpha, IL-1 beta, IL-1RA, or TNFalpha gene polymorphisms. No relationship was found between genotypes and the impulsivity of the suicide attempt. Estimated IL-1 haplotype frequencies were similar in both groups (likelihood ratio test=13.26, df=14, P=0.506). Our data do not suggest that genetically determined changes in the IL-1 or TNFalpha genes confer increased susceptibility to suicidal behavior.

  16. Tumor necrosis factor-alpha allele 2 shows an association with insulin-dependent diabetes mellitus in Latvians.

    Science.gov (United States)

    Shtauvere-Brameus, A; Dabadghao, P; Rumba, I; Sanjeevi, C B

    2002-04-01

    Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA-DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF-alpha) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF-alpha production and susceptibility to autoimmune and infectious diseases. Ninety-two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age- and sex-matched healthy controls were analyzed for the frequency of TNF-alpha alleles to test the hypothesis that TNF-alpha is associated with IDDM. We found that TNF-alpha microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF-alpha allele 2 with IDDM showed that both are independently associated with the disease.

  17. Characterization of a small molecule inhibitor of tumor necrosis factor-alpha production

    Institute of Scientific and Technical Information of China (English)

    YANG Gao-yun; XIE Zhi-qiang; QIAN Ge; CUI Wen-ying; ZHAO Jun-yin; ZHANG Jian-zhong; LIAN Shi

    2010-01-01

    Background Numerous studies have shown that reducing the level of tumor necrosis factor-alpha (TNFα) through the use of anti-TNF antibodies or soluble TNF receptor is a safe and efficacious treatment to inflammatory diseases such as rheumatoid arthritis. Therefore, novel approaches to achieve this outcome are desired. The aim of this study was to investigate the characterization of a small molecule inhibitor, Y316, which blocks TNF mRNA upregulation and TNF production by lipopolysaccharides (LPS) stimulated monocytes.Methods Peripheral blood mononuclear cells (PBMC) from healthy volunteers were plated in 24-well plates and stimulated with LPS (1 μg/ml), phorbol-12-myristate-13-acetate (PMA) (100 ng/ml), zymosan (10 μg/ml) and Tsst (100 ng/ml). Supernatants were collected after 4-hour culture at 37C, and quantitative determination of TNFα, interleukin-1β(IL-1β), IL-6, IL-8, IL-10 and IL-2 production in the supernatants was performed by colorimetric enzyme-linked immunosorbent assay (ELISA). Total RNA of PBMC was isolated and cytokine mRNA quantitation was performed by using a RNA level measuring kit (R & D Systems). PBMC were pretreated with Y316 (10 μmol/L, 1 μmol/L, 0.1 μmol/L,0.01 μmol/L and 0.001 μmol/L) or dimethyl sulfoxide at 37C for 10 minutes, and then stimulated with LPS or PMA,protein concentrations of p44.42, IKBα, P38 and Jun NH2-terminal kinase were determined by Western blotting. Cyclic adenosine-3',5'-monophosphate (cAMP) of PBMC was measured by enzyme immunoassay kit (Amersham Pharmacia Biotech).Results Y316 blocked TNF production and inhibited the upregulation of TNF mRNA levels in response to LPS, and also prevented the production of IL-1 and IL-6. In contrast, Y316 augmented the production of IL-10 in LPS-stimulated monocytes. Y316 failed to prevent the production of IL-2 and TNF in antigen-stimulated T cells, suggesting that its effects may be cell-type specific. Y316 prevented the phosphorylation and activation of the MAPK, ERK, and

  18. [Purification of recombinant proteins with an example of tumor necrosis factor thymosin-alpha1].

    Science.gov (United States)

    Fedorov, T V; Korobov, V I; Nazarov, V G; Smolkina, A E; Shmelev, V A

    2010-01-01

    Hybrid protein, cancer necrosis factor thymosin-alpha1 (CNF-T), when synthesizing in strain-producer of Escherichia coli SG200-50 with plasmid pThy315, was a part of "inclusion bodies" mostly in the form of a high-molecular complex with other proteins due to the S-S bonds formation. An approach of purification of CNF-T has been proposed, which is based on the destruction of the complex in the presence of sodium dodecylsulfate (DDS-NA) and dithiotreitol (DDT) followed by gel-filtration on Sephadex G-100 and renaturation by ultrafiltration on hollow fibers. The method allows the isolation of electrophoretically homogeneous CNF-T containing no DDS-Na and having high cytotoxic activity against cancer cells of mouse adenocarcinome L-929. The yield of CNF-T achieved 80% relative its content in biomass and 30% relative the total protein.

  19. Abnormal production of tumor necrosis factor (TNF) -- alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected].

    Science.gov (United States)

    Cortis, Elisabetta; De Benedetti, Fabrizio; Insalaco, Antonella; Cioschi, Stefania; Muratori, Flaminia; D'Urbano, Leila E; Ugazio, Alberto G

    2004-12-01

    We report a family with pyogenic sterile arthritis, pyoderna and acne syndrome (PAPA). The proband presented several episodes of sterile pyogenic arthritis and became unresponsive to glucocorticoids. After treatment with the tumor necrosis factor inhibitor etanercept, the disease underwent rapid and sustained clinical remission. Production of tumor necrosis factor-alpha by mononuclear cells of the proband and of the affected relatives was abnormally elevated.

  20. Quiescent interplay between inducible nitric oxide synthase and tumor necrosis factor-alpha: influence on transplant graft vasculopathy in renal allograft dysfunction.

    Science.gov (United States)

    Elahi, Maqsood M; Matata, Bashir M; Hakim, Nadey S

    2006-06-01

    A healthy endothelium is essential for vascular homeostasis, and preservation of endothelial cell function is critical for maintaining transplant allograft function. Damage to the microvascular endothelial cells is now regarded as a characteristic feature of acute vascular rejection, an important predictor of graft loss. It is also linked with transplant vasculopathy, often associated with chronic allograft nephropathy. Large bursts of nitric oxide in infiltrating monocytes/macrophages modulated by inducible nitric oxide synthase are considered pivotal in driving this mechanism. Indeed, it has been shown recently that increased circulating levels of tumor necrosis factor-alpha in the rejecting kidneys are largely responsible for triggering inducible nitric oxide synthase expression. This in turn suggests that several structural and functional features of graft rejection could be mediated by tumor necrosis factor-alpha. Despite the large body of evidence that supports immunologic involvement, knowledge concerning the cellular and biochemical mechanisms for nephritic cell dysfunction and death is incomplete. The role of tumor necrosis factor-alpha in mediating pathophysiological activity of inducible nitric oxide synthase during transplant vasculopathy remains contentious. Here, we discuss the effect of inducible nitric oxide synthase and tumor necrosis factor-alpha interaction on progressive damage to glomerular and vascular structures during renal allograft rejection. Selective inhibition of inducible nitrous oxide synthase and tumor necrosis factor-alpha as a potential therapy for ameliorating endothelial dysfunction and transplant graft vasculopathy is also discussed.

  1. Modulation of tumor necrosis factor {alpha} expression in mouse brain after exposure to aluminum in drinking water

    Energy Technology Data Exchange (ETDEWEB)

    Tsunoda, M.; Sharma, R.P. [Georgia Univ., Athens (Greece). College of Veterinary Medicine

    1999-11-01

    Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor {alpha} (TNF{alpha}), interleukin-1{beta} (IL-1{beta}), and interferon {gamma} (IFN{gamma}), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNF{alpha} mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNF{alpha} mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNF{alpha} in this brain region. Because the aluminum-induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water. (orig.)

  2. PROGNOSTIC VALUE OF TUMOR NECROSIS FACTOR-ALPHA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    E. N. Zotina

    2016-01-01

    Full Text Available The prognostic value of tumor necrosis factor-alfa (TNFα, a pro-inflammatory cytokine was studied in 140 patients with a newly diagnosed chronic lymphocytic leukemia (CLL. TNFα contents in blood serum was determined using ELISA method. A significant increase of serum TNFα was shown in patients with newly diagnosed CLL, as compared to healthy individuals. Dependence of the cytokine concentration on clnical stage and course of disease was revealed: the highest levels of serum TNFα were registered in patients with advanced disease and/or CLL progression. Distinct correlations were revealed between the studied cytokine amounts and clinical laboratory parameters reflecting the cell proliferative activity and tumor clone size. Immunochemotherapy was accompanied by a significant reduction of TNFα levels. According to the data from multivariate regression analysis. TNFα level of at the time of the diagnosis was an independent predictor of overall survival. Hence, TNFα plays an important role in CLL pathogenesis and may be used as an additional predictive factor for CLL outcomes.

  3. Human cytomegalovirus infection inhibits tumor necrosis factor alpha (TNF-alpha) signaling by targeting the 55-kilodalton TNF-alpha receptor.

    Science.gov (United States)

    Baillie, J; Sahlender, D A; Sinclair, J H

    2003-06-01

    Infection with human cytomegalovirus (HCMV) results in complex interactions between viral and cellular factors which perturb many cellular functions. HCMV is known to target the cell cycle, cellular transcription, and immunoregulation, and it is believed that this optimizes the cellular environment for viral DNA replication during productive infection or during carriage in the latently infected host. Here, we show that HCMV infection also prevents external signaling to the cell by disrupting the function of TNFRI, the 55-kDa receptor for tumor necrosis factor alpha (TNF-alpha), one of the receptors for a potent cytokine involved in eliciting a wide spectrum of cellular responses, including antiviral responses. HCMV infection of fully permissive differentiated monocytic cell lines and U373 cells resulted in a reduction in cell surface expression of TNFRI. The reduction appeared to be due to relocalization of TNFRI from the cell surface and was reflected in the elimination of TNF-alpha-induced Jun kinase activity. Analysis of specific phases of infection suggested that viral early gene products were responsible for this relocalization. However, a mutant HCMV in which all viral gene products known to be involved in down-regulation of major histocompatibility complex (MHC) class I were deleted still resulted in relocalization of TNFRI. Consequently, TNFRI relocalization by HCMV appears to be mediated by a novel viral early function not involved in down-regulation of cell surface MHC class I expression. We suggest that upon infection, HCMV isolates the cell from host-mediated signals, forcing the cell to respond only to virus-specific signals which optimize the cell for virus production and effect proviral responses from bystander cells.

  4. Ribozyme modulation of lipopolysaccharide-induced tumor necrosis factor-alpha production by peritoneal cells in vitro and in vivo.

    Science.gov (United States)

    Sioud, M

    1996-05-01

    We have utilized synthetic ribozymes to modulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha) by peritoneal cells. Two hammerhead ribozymes (mRz1 and mRz2) were prepared by transcription in vitro and their activities in vitro and in vivo were investigated. Both ribozymes cleaved their RNA target with an apparent turnover number (kcat) of 2 min(-1), and inhibited TNF-alpha gene expression in vitro by 50% and 70%, respectively. When mRz1 and mRz2, entrapped in liposomes, were delivered into mice by intraperitoneal injection, they inhibited LPS-induced TNF-alpha gene expression in vivo with mRz2 being the most effective. This enhanced activity could result from the facilitation of catalysis by cellular endogenous proteins, since they specifically bind to mRz2 as compared to mRz1. Furthermore, a significant mRz2 activity can be recovered from peritoneal cells 2 days post-administration in vivo. The anti-TNF-alpha ribozyme treatment in vivo resulted in a more significant reduction of LPS-induced IFN-gamma protein secretion compared to IL-10. In contrast to this pleiotropic effect, the anti-TNF-alpha ribozyme treatment did not affect the heterogenous expression of Fas ligand by peritoneal cells, indicating the specificity of the treatment. Taken together, the present data indicate that the biological effects of TNF-alpha can be modulated by ribozymes. In addition, the data suggest that ribozymes can be administered in a drug-like manner, and therefore indicate their potential in clinical applications.

  5. Sensitization of voltage activated calcium channel currents for capsaicin in nociceptive neurons by tumor-necrosis-factor-alpha.

    Science.gov (United States)

    Hagenacker, T; Czeschik, J C; Schäfers, M; Büsselberg, D

    2010-01-15

    It is known that application of tumor-necrosis-factor-alpha (TNF-alpha) sensitizes neuronal calcium channels for heat stimuli in rat models of neuropathic pain. This study examines whether TNF-alpha modulates the capsaicin-induced effects after transient receptor potential vanilloid (TRPV)-1 receptor activation on voltage activated calcium channel currents (I(Ca(V))). TRPV-1 receptors are activated by heat and play an important role in the pathogenesis of thermal hyperalgesia in neuropathic pain syndromes, while voltage activated channels are essential for transmission of neuronal signals. Eliciting I(Ca(V)) in DRG neurons of rats by a depolarization from the resting potential to 0 mV, TNF-alpha (100 ng/ml) reduces I(Ca(V)) by 16.9+/-2.2%, while capsaicin (0.1 microM) decreases currents by 27+/-4.3%. Pre-application of TNF-alpha (100 ng/ml) for 24h results in a sensitization of I(Ca(V)) to capsaicin (0.1 microM) with a reduction of 42.8+/-4.4% mediated by TRPV-1. While L-type (36.6+/-5.2%) and P/Q-type currents (35.6+/-4.1%) are also sensitized by TRPV-1 activation, N-type channel currents are most sensitive (74.5+/-7.3%). The capsaicin-induced shift towards the hyperpolarizing voltage range does not occur when TNF-alpha is applied. Summarizing, TNF-alpha sensitizes nociceptive neurons for capsaicin.

  6. Tumor necrosis factor alpha inhibits in vitro bovine embryo development through a prostaglandin mediated mechanism

    Directory of Open Access Journals (Sweden)

    Jackson Lauren R

    2012-03-01

    Full Text Available Abstract Mastitis or other infectious diseases have been related to reduced fertility in cattle. Inflammatory cytokines such as tumor necrosis factor α (TNFα are released in response to infection and may have negative effects on embryo development. In the current study the effect of exposure to TNFα on the development of in vitro fertilized bovine embryos was examined. Indomethacin, a prostaglandin synthesis inhibitor, was used to determine if blockade of prostaglandin synthesis would alter the effects of TNFα. Ovaries were obtained from a local abattoir and immature COC were isolated from 2-10 mm follicles, in vitro matured and fertilized. After fertilization, groups of presumptive zygotes were randomly placed into either control development medium, medium containing 25 ng/mL TNFα or medium containing 25 ng/mL TNFα plus 1 μg/mL indomethacin. The proportion of blastocysts formed was assessed at day 7 of culture. Fewer embryos exposed to TNFα alone reached the blastocyst stage (17.5 ± 2.4%, P

  7. Construction of novel tumor necrosis factor-alpha mutants with reduced toxicity and higher cytotoxicity on human tumor cells

    Institute of Scientific and Technical Information of China (English)

    LIU; Hui; (刘; 惠); LU; Fang; (卢; 芳); CHEN; Jianjun; (陈建军); REN; Hongyu; (任红玉); CHEN; Changqing(陈常庆)

    2003-01-01

    Two tumor necrosis factor-( mutants MT1 (32Trp157Phe) and MT2 (2Lys30Ser- 32Trp157Phe) were constructed by site-directed mutagenesis. These mutants were soluble and over-expressed in E. coli. The purity of purified mutants was above 95% by serial chromatography. The results of Western blot indicated that these mutants could be cross-reactive with monoclonal antibody against native hTNF-α. Compared to parent hTNF-α, the cytotoxicity of these mutants on murine fibrosarcoma L929 cell lines reduced 4-5 orders of magnitude but was equivalent to that of native hTNF-α on human tumor cell lines. The LD50 of mutant MT1 was reduced to 0.34% of wild type and the dose of MT2 that resulted in 30% death of mice reduced to less than 1/700 that of parent hTNF-α.

  8. Phospholipase C-{delta}{sub 1} regulates interleukin-1{beta} and tumor necrosis factor-{alpha} mRNA expression

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eric; Jakinovich, Paul; Bae, Aekyung [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States); Rebecchi, Mario, E-mail: Mario.rebecchi@SBUmed.org [Department of Anesthesiology, Health Sciences Center L4 Rm 081, Stony Brook University, Stony Brook, NY 11794 (United States)

    2012-10-01

    Phospholipase C-{delta}{sub 1} (PLC{delta}{sub 1}) is a widely expressed highly active PLC isoform, modulated by Ca{sup 2+} that appears to operate downstream from receptor signaling and has been linked to regulation of cytokine production. Here we investigated whether PLC{delta}{sub 1} modulated expression of the pro-inflammatory cytokines interleukin-1{beta} (IL-1{beta}), tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) in rat C6 glioma cells. Expression of PLC{delta}{sub 1} was specifically suppressed by small interfering RNA (siRNA) and the effects on cytokine mRNA expression, stimulated by the Toll-like receptor (TLR) agonist, lipopolysaccharide (LPS), were examined. Real-time polymerase chain reaction (RT-PCR) results showed that PLC{delta}{sub 1} knockdown enhanced expression IL-1{beta} and tumor necrosis factor-{alpha} (TNF-{alpha}) mRNA by at least 100 fold after 4 h of LPS stimulation compared to control siRNA treatment. PLC{delta}{sub 1} knock down caused persistently high Nf{kappa}b levels at 4 h of LPS stimulation compared to control siRNA-treated cells. PLC{delta}{sub 1} knockdown was also associated with elevated nuclear levels of c-Jun after 30 min of LPS stimulation, but did not affect LPS-stimulated p38 or p42/44 MAPK phosphorylation, normally associated with TLR activation of cytokine gene expression; rather, enhanced protein kinase C (PKC) phosphorylation of cellular proteins was observed in the absence of LPS stimulation. An inhibitor of PKC, bisindolylmaleimide II (BIM), reversed phosphorylation, prevented elevation of nuclear c-Jun levels, and inhibited LPS-induced increases of IL-1{beta} and TNF-{alpha} mRNA's induced by PLC{delta}{sub 1} knockdown. Our results show that loss of PLC{delta}{sub 1} enhances PKC/c-Jun signaling and up-modulates pro-inflammatory cytokine gene transcription in concert with the TLR-stimulated p38MAPK/Nf{kappa}b pathway. Our findings are consistent with the idea that PLC{delta}{sub 1} is a

  9. Apoptotic neutrophils containing Staphylococcus epidermidis stimulate macrophages to release the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6.

    Science.gov (United States)

    Wilsson, Asa; Lind, Sara; Ohman, Lena; Nilsdotter-Augustinsson, Asa; Lundqvist-Setterud, Helen

    2008-06-01

    Staphylococcus epidermidis infections are usually nosocomial and involve colonization of biomaterials. The immune defense system cannot efficiently control the bacteria during these infections, which often results in protracted chronic inflammation, in which a key event is disturbed removal of neutrophils by tissue macrophages. While ingesting uninfected apoptotic neutrophils, macrophages release anti-inflammatory cytokines that lead to resolution of inflammation. In clinical studies, we have previously found elevated levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in synovial fluid from prostheses infected with coagulase negative staphylococci. We show that macrophages phagocytosing apoptotic neutrophils containing S. epidermidis released TNF-alpha and interleukin-6, whereas macrophages phagocytosing spontaneously apoptotic neutrophils did not. This difference was not due to dissimilar phagocytic capacities, because macrophages ingested both types of neutrophils to the same extent. The activation was induced mainly by the apoptotic neutrophils themselves, not by the few remaining extracellular bacteria. Macrophages were not activated by apoptotic neutrophils that contained paraformaldehyde-killed S. epidermidis. Proinflammatory reactions induced by clearance of apoptotic neutrophils containing S. epidermidis might represent an important mechanism to combat the infective agent. This activation of macrophages may contribute to the development of chronic inflammation instead of inflammation resolution.

  10. Single nucleotide polymorphism in the tumor necrosis factor-alpha gene affects inflammatory bowel diseases risk

    Institute of Scientific and Technical Information of China (English)

    Lynnette R Ferguson; Claudia Huebner; Ivonne Petermann; Richard B Gearry; Murray L Barclay; Pieter Demmers; Alan McCulloch; Dug Yeo Han

    2008-01-01

    AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies.METHODS: DNA samples from 388 patients with Crohn's disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor:-238 G→A, -308 G→A and -857C→T, using a TaqmanRassay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies.RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, x2 = 17.36, P < 0.0001)increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, x2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variantdecreased the risk of ileocolonic CD (OR = 0.56, x2 =4.32, P = 0.037), and the need for a bowel resection(OR = 0.59, x2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis,(OR = 0.48, x2 = 4.86, P = 0.028).CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The-857 C/T SNP may decrease IBD risk in certain groups.Pharmaco- or nutrigenomic approaches may be desir-able for individuals with such affected genotypes.

  11. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-[alpha

    Energy Technology Data Exchange (ETDEWEB)

    Carter, Percy H.; Scherle, Peggy A.; Muckelbauer, Jodi K.; Voss, Matthew E.; Liu, Rui-qin; Thompson III, Lorin A.; Xu, Meizhong; Lo, Yvonne C.; Li, Zhong; Strzemienski, Paul; Yang, Gengjie; Falahatpishen, Nikoo; Farrow, Neil A.; Tebben, Andrew J.; Underwood, Denis; Trzaskos, James M.; Friedman, Steven M.; Newton, Robert C.; Decicco, Carl P. (DuPont)

    2010-03-05

    The binding of tumor necrosis factor alpha (TNF-{alpha}) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-{alpha} to TNFRc1 (IC{sub 50} = 50 nM) and also blocked TNF-stimulated phosphorylation of I{kappa}-B in Ramos cells (IC{sub 50} = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 {micro}M. Detailed evaluation of this and related molecules revealed that compounds in this class are 'photochemically enhanced' inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 mM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-{alpha} to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-{alpha}-TNFRc1 interaction.

  12. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.

    Science.gov (United States)

    Carter, P H; Scherle, P A; Muckelbauer, J K; Voss, M E; Liu, R Q; Thompson, L A; Tebben, A J; Solomon, K A; Lo, Y C; Li, Z; Strzemienski, P; Yang, G; Falahatpisheh, N; Xu, M; Wu, Z; Farrow, N A; Ramnarayan, K; Wang, J; Rideout, D; Yalamoori, V; Domaille, P; Underwood, D J; Trzaskos, J M; Friedman, S M; Newton, R C; Decicco, C P; Muckelbauer, J A

    2001-10-09

    The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.

  13. Cytokine production in the central nervous system of Lewis rats with experimental autoimmune encephalomyelitis: dynamics of mRNA expression for interleukin-10, interleukin-12, cytolysin, tumor necrosis factor alpha and tumor necrosis factor beta

    DEFF Research Database (Denmark)

    Issazadeh-Navikas, Shohreh; Ljungdahl, A; Höjeberg, B

    1995-01-01

    in cryosections of spinal cords using in situ hybridization technique with synthetic oligonucleotide probes. Three stages of cytokine mRNA expression could be distinguished: (i) interleukin (IL)-12, tumor necrosis factor (TNF)-beta (= lymphotoxin-alpha) and cytolysin appeared early and before onset of clinical...... signs of EAE; (ii) TNF-alpha peaked at height of clinical signs of EAE; (iii) IL-10 appeared increasingly at and after clinical recovery. The early expression of IL-12 prior to the expression of interferon-gamma (IFN-gamma) mRNA shown previously is consistent with a role of IL-12 in promoting...... proliferation and activation of T helper 1 (Th1) type cells producing IFN-gamma. The TNF-beta mRNA expression prior to onset of clinical signs favours a role for this cytokine in disease initiation. A pathogenic effector role of TNF-alpha was suggested from these observations that TNF-alpha mRNA expression...

  14. Isolated limb perfusion with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma : Three time periods at risk for amputation

    NARCIS (Netherlands)

    van Ginkel, Robert J.; Thijssens, Katja M. J.; Pras, Elisabeth; Van der Graaf, Winette T. A.; Suurmeijer, Albert J. H.; Hoekstra, Harald J.

    2007-01-01

    Background: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods: From 1991 to 2003, 73 patients (36 men, 37 women, medi

  15. Pretreatment with high-fat enteral nutrition reduces ondotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock

    NARCIS (Netherlands)

    Luyer, M.D.; Buurman, W.A.; Hadfoune, M.; Jacobs, J.A.; Konstantinov, S.R.; Dejong, C.H.; Greve, J.W.

    2004-01-01

    Gram-negative sepsis is a potentially fatal clinical syndrome characterized by a proinflammatory response (tumor necrosis factor-alpha) to bacterial (endo)toxins and gut barrier function loss. Recently, we found that high-fat enteral nutrition protects against late bacterial translocation in a model

  16. Plasma endothelin-1 and tumor necrosis factor-alpha concentrations in pregnant and cyclic rats after low-dose endotoxin infusion

    NARCIS (Netherlands)

    Faas, MM; Bakker, WW; Valkhof, N; Baller, JFW; Schuiling, GA

    1997-01-01

    Plasma endothelin-1 and tumor necrosis factor-alpha were determined in pregnant and cyclic rats after infusion of either endotoxin (1.0 mu g/kg of body weight) or saline solution. After endotoxin, but not after saline solution, administration there was a transient endothelin-1 response in pregnant r

  17. ONO 3403, a synthetic serine protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production and protects mice from lethal endotoxic shock

    NARCIS (Netherlands)

    Tumurkhuu, Gantsetseg; Koide, Naoki; Hiwasa, Takaki; Ookoshi, Motohiro; Dagvadorj, Jargalsaikhan; Noman, Abu Shadat Mohammod; Iftakhar-E-Khuda, Imtiaz; Naiki, Yoshikazu; Komatsu, Takayuki; Yoshida, Tomoaki; Yokochi, Takashi

    2011-01-01

    ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha and nitric oxide (NO) production in RAW 264.7 macrophage-like cells wa

  18. The effect of chronic periodontitis on serum levels of tumor necrosis factor-alpha in Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Shirin Zahra Farhad

    2014-01-01

    Full Text Available Background: Despite the outbreak in dental science, oral and dental complications in Alzheimer are of the unsolved problems. It is assumed that tumor necrosis factor-α, which is a key factor in Alzheimer, has a relation with periodontal complications in patients with Alzheimer disease. The present study evaluated the effect of chronic periodontitis on serum levels of tumor necrosis factor-α in Alzheimer disease. Materials and Methods: This case-control study was performed on 80 patients with Alzheimer disease seeking medical care at Nour Hospital, Isfahan, Iran. Eighty patients with Alzheimer disease between 40 and 70 years old attended this study. Forty had chronic periodontitis (case group, and 40 patients had healthy periodontium (control group. Blood sample was taken, and serum levels of tumor necrosis factor-α were measured by means of an ELISA Reader device. Independent T-Test was used to analyze data, and P < 0.05 was considered significant. Results: The mean of tumor necrosis factor-α was 749.1 ng/μL in case group and 286.8 ng/μL in control group. Independent t-test showed that the mean of tumor necrosis factor-α in patients with Alzheimer and periodontitis was approximately three folds higher than the patients only with Alzheimer, and this difference was statistically significant (P < 0.001. Conclusion: According to the results of this study, it seems that there is a difference between serum levels of tumor necrosis factor-α in patient with Alzheimer and chronic periodontitis and patients with Alzheimer disease and healthy periodontium. Tumor necrosis factor-α level in serum may act as a diagnostic marker of periodontal disease in patients with Alzheimer disease

  19. Inhibitory activity of the white wine compounds, tyrosol and caffeic acid, on lipopolysaccharide-induced tumor necrosis factor-alpha release in human peripheral blood mononuclear cells.

    Science.gov (United States)

    Giovannini, L; Migliori, M; Filippi, C; Origlia, N; Panichi, V; Falchi, M; Bertelli, A A E; Bertelli, A

    2002-01-01

    The objective of this study was to assess whether tyrosol and caffeic acid are able to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release. TNF is one of the most important cytokines involved in inflammatory reactions. The results show that both tyrosol and caffeic acid are able to inhibit LPS-induced TNF-alpha release from human monocytes, even at low doses. Their mechanisms of action are discussed and we conclude that high doses of the two compounds are not required to achieve effective inhibition of inflammatory reactions due to TNF-alpha release.

  20. Evaluation of salivary tumor necrosis factor-alpha in patients with the chronic periodontitis: A case-control study

    Directory of Open Access Journals (Sweden)

    Hojatollah Yousefimanesh

    2013-01-01

    Full Text Available Context: Periodontitis is a chronic infectious disease that leads to inflammation of the tissues supporting the teeth, bone loss, attachment loss progressively. In chronic periodontitis for starting the host response and inflammatory reaction, the presence of the infectious agent is necessary. Aims: One of inflammatory factors is tumor necrosis factor-alpha (TNF-α that appear to be important in the destruction of periodontal tissues that were examined in this study. Materials and Methods: This study was performed in the laboratory and case-control study. The samples of study collected from 30 individuals with chronic periodontitis and 30 healthy controls that matched for age and sex, together. Unstimulated saliva samples were collected from patients and then TNF-α level were measured by enzyme-linked immunosorbent assay and were compared with the control group. Statistical Analysis Used: In this study for statistical analysis, Mann-Whitney was used. Results: There were differences in mean salivary concentrations of TNF-α in controls and patients. The average concentration in the case group was 9.1 (pg/ml and the control group was 8.7 (pg/ml, but there was no significant difference between case and control groups (P > 0.05. Conclusions: The results of this analysis showed no significant relationship between two groups TNF-α concentration.This biomarker can not seem to be a good index to evaluate or predict periodontal disease.

  1. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses.

    Science.gov (United States)

    Chen, Yuehong; Sun, Jianhong; Yang, Yuan; Huang, Yupeng; Liu, Gang

    2016-01-01

    The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.

  2. Establishment and evaluation of a transgenic mouse model of arthritis induced by overexpressing human tumor necrosis factor alpha

    Directory of Open Access Journals (Sweden)

    Ge Li

    2016-04-01

    Full Text Available Tumor necrosis factor alpha (TNFα plays a key role in the pathogenesis of rheumatoid arthritis (RA. Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.

  3. Facile purification of Escherichia coli expressed tag-free recombinant human tumor necrosis factor alpha from supernatant.

    Science.gov (United States)

    Zhang, Chun; Liu, Yongdong; Zhao, Dawei; Li, Xiunan; Yu, Rong; Su, Zhiguo

    2014-03-01

    Fusing affinity tag at N-terminus was reported to decrease the biological activity of the recombinant human tumor necrosis factor alpha. Although preparation of tag-free rhTNF-α has already been achieved, the processes were yet laborious, especially in large scale. In this paper, tag-free rhTNF-α was almost equally synthesized by Escherichia coli in both soluble and insoluble forms. A two-step ion exchange chromatography, DEAE-Sepharose combined with CM-Sepharose, was developed to purify the soluble specie from supernatant after cell lysis. Native PAGE and HP-SEC showed the rhTNF-α extracted from supernatant existed in a homogeneous form. HP-SAX and SDS-PAGE analysis demonstrated the purity of the final fraction was over 98% with a very high recovery of 75%. Circular dichroism spectrum demonstrated that β-sheet structure was dominant and fluorescence analysis suggested no dramatic exposure of aromatic amino acid residues on the protein surface. Bioassay indicated that purified rhTNF-α was biologically active with a specific activity of approximately 2.0×10(7)U/mg. All these results suggested that this two-step ion exchange chromatography is efficient for preparation of biologically active tag-free rhTNF-α from supernatant.

  4. Pathophysiological roles of microvascular alterations in pulmonary inflammatory diseases: possible implications of tumor necrosis factor-alpha and CXC chemokines

    Directory of Open Access Journals (Sweden)

    Kanami Orihara

    2008-10-01

    Full Text Available Kanami Orihara, Akio MatsudaDepartment of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, JapanAbstract: Chronic obstructive pulmonary disease (COPD and bronchial asthma are common respiratory diseases that are caused by chronic infl ammation of the airways. Although these diseases are mediated by substantially distinct immunological reactions, especially in mild cases, they both show increased numbers of neutrophils, increased production of tumor necrosis factor-alpha (TNF-α and poor responses to corticosteroids, particularly in patients with severe diseases. These immunological alterations may contribute strongly to airway structural changes, commonly referred to as airway remodeling. Microvascular alterations, a component of airway remodeling and caused by chronic inflammation, are observed and appear to be clinically involved in both diseases. It has been well established that vascular endothelial growth factor (VEGF plays important roles in the airway microvascular alterations in mild and moderate cases of both diseases, but any role that VEGF might play in severe cases of these diseases remains unclear. Here, we review recent research findings, including our own data, and discuss the possibility that TNF-α and its associated CXC chemokines play roles in microvascular alterations that are even more crucial than those of VEGF in patients with severe COPD or asthma.Keywords: TNF-α, CXC chemokines, corticosteroid, pulmonary microvessels, COPD, asthma

  5. Effect of tumor necrosis factor-alpha in rats with hepatic ischemia-reper fusion injur y

    Institute of Scientific and Technical Information of China (English)

    Mao Ma; Zhen-Hua Ma

    2008-01-01

    BACKGROUND:With the development of hepatic surgery, especially liver transplantation, the pathophysiological processes of hepatic ischemia-reperfusion (I/R) injury have gained special attention. Controlling I/R injury has become one of the most important factors for successful liver transplantation. This study aimed to investigate the effects of tumor necrosis factor-alpha (TNF-α) in rats with hepatic I/R injury and promote the recognition of I/R injury in the liver. METHODS:Thirty-two Sprague-Dawley rats were randomly divided into 2 groups. Rats in the sham-operated (SO) group served as controls. Rats in the hepatic ischemia-reperfusion (I/R) group underwent reperfusion after 30 minutes of liver ischemia. Rats were sacriifced at 1, 6 and 12 hours. The expression of TNF-αmRNA in the liver was measured by RT-PCR. Histological changes in the liver were assessed. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were measured. RESULTS:The expression of TNF-αmRNA in the SO group was decreased compared with that in the I/R group (P CONCLUSION:ALT and AST in serum are closely related to hepatic I/R injury and inlfammatory reaction. TNF-αproduction in the liver triggers hepatic I/R injury through a cascade.

  6. Garlic (Allium sativum) stimulates lipopolysaccharide-induced tumor necrosis factor-alpha production from J774A.1 murine macrophages.

    Science.gov (United States)

    Sung, Jessica; Harfouche, Youssef; De La Cruz, Melissa; Zamora, Martha P; Liu, Yan; Rego, James A; Buckley, Nancy E

    2015-02-01

    Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion.

  7. Modulator effects of interleukin-1beta and tumor necrosis factor-alpha on AMPA-induced excitotoxicity in mouse organotypic hippocampal slice cultures

    DEFF Research Database (Denmark)

    Bernardino, Liliana; Xapelli, Sara; Silva, Ana P

    2005-01-01

    The inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) have been identified as mediators of several forms of neurodegeneration in the brain. However, they can produce either deleterious or beneficial effects on neuronal function. We investigated the effects...... of mouse recombinant TNF-alpha (10 ng/ml) enhanced excitotoxicity when the cultures were simultaneously exposed to AMPA and to this cytokine. Decreasing the concentration of TNF-alpha to 1 ng/ml resulted in neuroprotection against AMPA-induced neuronal death independently on the application protocol....... By using TNF-alpha receptor (TNFR) knock-out mice, we demonstrated that the potentiation of AMPA-induced toxicity by TNF-alpha involves TNF receptor-1, whereas the neuroprotective effect is mediated by TNF receptor-2. AMPA exposure was associated with activation and proliferation of microglia as assessed...

  8. In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha).

    Science.gov (United States)

    Trombetta, Domenico; Cimino, Francesco; Cristani, Mariateresa; Mandalari, Giuseppina; Saija, Antonella; Ginestra, Giovanna; Speciale, Antonio; Chirafisi, Joselita; Bisignano, Giuseppe; Waldron, Keith; Narbad, Arjan; Faulds, Craig B

    2010-07-28

    Bergamot ( Citrus bergamia Risso) is a less commercialized Citrus fruit, mainly used for its essential oil extracted from the peel. Bergamot peel (BP) represents about 60% of the processed fruits and is regarded as primary waste. However, it contains good amounts of useful compounds, such as pectins and flavonoids. Many of the bioactivities of Citrus flavonoids appear to impact vascular endothelial cells. Herein, we report the protective effect of two flavonoid-rich extracts from BP (endowed with radical-scavenging properties and lacking genotoxic activity) against alterations in cell modifications induced by the pleiotropic inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on human umbilical vein endothelial cells (HUVECs), as demonstrated by monitoring intracellular levels of malondialdehyde/4-hydroxynonenal, reduced and oxidized glutathione and superoxide dismutase activity, and the activation status of nuclear factor-kappaB (NF-kappaB). Thus, BP appears to be a potential source of natural antioxidant/anti-inflammatory phytocomplexes to be employed as ingredients of nutraceutical products or functional foods.

  9. Activity and tissue-specific expression of lipases and tumor-necrosis factor alpha in lean and obese cats.

    NARCIS (Netherlands)

    Hoenig, M.; McGoldrick, J.B.; Beer, M. de; Demacker, P.N.M.; Ferguson, D.C.

    2006-01-01

    Post-heparin plasma activity of lipoprotein lipase (LPL) and hepatic lipase (HL), and fat and muscle activity of LPL were measured in neutered lean and obese cats. Lipoprotein lipase, hormone-sensitive lipase (HSL), and tumor necrosis factor a (TNF) mRNA were measured in muscle and fat tissue with r

  10. The tumor necrosis factor alpha -308G>A polymorphism is associated with dementia in the oldest old

    DEFF Research Database (Denmark)

    Bruunsgaard, Helle; Benfield, Thomas L; Andersen-Ranberg, Karen;

    2004-01-01

    OBJECTIVES: To test the hypothesis that the tumor necrosis factor (TNF) -308 G>A promoter gene polymorphism is a risk factor in age-related dementia and longevity. DESIGN: A cross-sectional and a longitudinal study. SETTING: A population-based sample of Danish centenarians. PARTICIPANTS: One...

  11. Modulation of Anti-Tumor Necrosis Factor Alpha (TNF-α) Antibody Secretion in Mice Immunized with TNF-α Kinoid

    OpenAIRE

    Assier, Eric; Semerano, Luca; Duvallet, Emilie; Delavallée, Laure; Bernier, Emilie; Laborie, Marion; Grouard-Vogel, Géraldine; Larcier, Patrick; Bessis, Natacha; Boissier, Marie-Christophe

    2012-01-01

    Tumor necrosis factor alpha (TNF-α) blockade is an effective treatment for patients with TNF-α-dependent chronic inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-α kinoid, a heterocomplex of human TNF-α and keyhole limpet hemocyanin (KLH) (TNF-K), is an active immunotherapy targeting TNF-α. Since the TNF-K approach is an active immunization, and patients receiving this therapy also receive immunosuppressant treatment, we evaluated the effect of some imm...

  12. Tumor necrosis factor alpha production from CD8+ T cells mediates oviduct pathological sequelae following primary genital Chlamydia muridarum infection.

    Science.gov (United States)

    Murthy, Ashlesh K; Li, Weidang; Chaganty, Bharat K R; Kamalakaran, Sangamithra; Guentzel, M Neal; Seshu, J; Forsthuber, Thomas G; Zhong, Guangming; Arulanandam, Bernard P

    2011-07-01

    The immunopathogenesis of Chlamydia trachomatis-induced oviduct pathological sequelae is not well understood. Mice genetically deficient in perforin (perforin(-/-) mice) or tumor necrosis factor alpha (TNF-α) production (TNF-α(-/-) mice) displayed comparable vaginal chlamydial clearance rates but significantly reduced oviduct pathology (hydrosalpinx) compared to that of wild-type mice. Since both perforin and TNF-α are effector mechanisms of CD8(+) T cells, we evaluated the role of CD8(+) T cells during genital Chlamydia muridarum infection and oviduct sequelae. Following vaginal chlamydial challenge, (i) mice deficient in TAP I (and therefore the major histocompatibility complex [MHC] I pathway and CD8(+) T cells), (ii) wild-type mice depleted of CD8(+) T cells, and (iii) mice genetically deficient in CD8 (CD8(-/-) mice) all displayed similar levels of vaginal chlamydial clearance but significantly reduced hydrosalpinx, compared to those of wild-type C57BL/6 mice, suggesting a role for CD8(+) T cells in chlamydial pathogenesis. Repletion of CD8(-/-) mice with wild-type or perforin(-/-), but not TNF-α(-/-), CD8(+) T cells at the time of challenge restored hydrosalpinx to levels observed in wild-type C57BL/6 mice, suggesting that TNF-α production from CD8(+) T cells is important for pathogenesis. Additionally, repletion of TNF-α(-/-) mice with TNF-α(+/+) CD8(+) T cells significantly enhanced the incidence of hydrosalpinx and oviduct dilatation compared to those of TNF-α(-/-) mice but not to the levels found in wild-type mice, suggesting that TNF-α production from CD8(+) T cells and non-CD8(+) cells cooperates to induce optimal oviduct pathology following genital chlamydial infection. These results provide compelling new evidence supporting the contribution of CD8(+) T cells and TNF-α production to Chlamydia-induced reproductive tract sequelae.

  13. Tumor necrosis factor-alpha inhibitor combined with methotrexate for ankylosing spondylitis: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Shaopeng Lin

    2014-06-01

    Full Text Available To evaluate the benefits and harms of combination of tumor necrosis factor-alpha (TNF-α inhibitor and methotrexate (MTX compared with TNF-α inhibitor monotherapy in the treatment of ankylosing spondylitis (AS. Randomized controlled trials were identified from Medline, Embase, Cinahl, Central and Clinical Trials Registry Platform, as well as from the reference sections of retrieved articles. The risk of bias was evaluated in all included trials. Data were extracted by two reviewers independently using a specially designed extraction form. The Cochrane Collaboration’s Review Manager 5.2 software was used for data analysis. The search retrieved 852 titles, of which 3 original trials were included, involving 187 participants. The overall risk of bias is low in all three trials. Only one study was placebo controlled, and all of them examined small samples. The analysis showed no significant advantage of the MTX combination versus monotherapy. Two trials assessed Assessment of Ankylosing Spondylitis (ASAS 40 and the pooled risk ratio (RR was 1.37 and 95% confidence interval 0.84 to 2.23. The RR for ASAS20 was 1.16 (0.88 to 1.52. Likewise, there were no significant difference between two groups in partial remission, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Magnetic resonance imaging activity score and other secondary outcomes. Withdrawals for side effects and for any reason were similar in two groups, RR were 1.89 (0.71 to 5.02 and 1.11 (0.67 to 1.84, respectively. The evidence available did not support any benefit of adding MTX to TNF-α inhibitor for the treatment of AS.

  14. Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein 1 Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population

    Institute of Scientific and Technical Information of China (English)

    Jian-Wen Han; Yong Wang; Chulu Alateng; Hong-Bin Li; Yun-Hua Bai; Xin-Xiang Lyu; Rina Wu

    2016-01-01

    Background:Psoriasis is a common immune-mediated inflammatory dermatosis.Generalized pustular psoriasis (GPP) is the severe and rare type of psoriasis.The association between tumor necrosis factor-alpha induced protein 3 interacting protein 1 (TNIP1) gene and psoriasis was confirmed in people with multiple ethnicities.This study was to investigate the association between TNIP1 gene polymorphisms and pustular psoriasis in Chinese Han population.Methods:Seventy-three patients with GPP,67 patients with palmoplantar pustulosis (PPP),and 476 healthy controls were collected from Chinese Han population.Six single nucleotide polymorphisms (SNPs) of the TNIP1 gene,namely rs3805435,rs3792798,rs3792797,rs869976,rs17728338,and rs999011 were genotyped by using polymerase chain reaction-ligase detection reaction.Statistical analyses were performed using the PLINK 1.07 package.Allele frequencies and genotyping frequencies for six SNPs were compared by using Chi-square test,odd ratio (OR) (including 95% confidence interval) were calculated.The haplotype analysis was conducted by Haploview software.Results:The frequencies of alleles of five SNPs were significantly different between the GPP group and the control group (P≤ 7.22 × 10-3),especially in the GPP patients without psoriasis vulgaris (PsV).In the haplotype analysis,the most significantly different haplotype was H4:ACGAAC,with 13.1% frequency in the GPP group but only 3.4% in the control group (OR =4.16,P =4.459 × 10-7).However,no significant difference in the allele frequencies was found between the PPP group and control group for each of the six SNPs (P > 0.05).Conclusions:Polymorphisms in TNIP1 are associated with GPP in Chinese Han population.However,no association with PPP was found.These findings suggest that TNIP1 might be a susceptibility gene for GPP.

  15. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OHD concentrations in healthy women

    Directory of Open Access Journals (Sweden)

    Heffernan Mary E

    2008-07-01

    Full Text Available Abstract Background Circulating 25 hydroxyvitamin D (25 (OHD, an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH D concentrations and inflammatory markers in healthy women. Methods This observational study included 69 healthy women, age 25–82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OHD concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OHD, parathyroid hormone (iPTH, estradiol (E2, cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-α, interleukin-6 and -10 (IL-6, IL-10, and C-reactive protein (CRP]. Results Women with regular UVB exposure (Hi-D had serum 25(OHD concentrations that were significantly higher (p p Conclusion Serum 25(OHD status is inversely related to TNF-α concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.

  16. Eugenol reduces acute pain in mice by modulating the glutamatergic and tumor necrosis factor alpha (TNF-α) pathways.

    Science.gov (United States)

    Dal Bó, Wladmir; Luiz, Ana Paula; Martins, Daniel F; Mazzardo-Martins, Leidiane; Santos, Adair R S

    2013-10-01

    Eugenol is utilized together with zinc oxide in odontological clinical for the cementation of temporary prostheses and the temporary restoration of teeth and cavities. This work explored the antinociceptive effects of the eugenol in different models of acute pain in mice and investigated its possible modulation of the inhibitory (opioid) and excitatory (glutamatergic and pro-inflammatory cytokines) pathways of nociceptive signaling. The administration of eugenol (3-300 mg/kg, p.o., 60 min or i.p., 30 min) inhibited 82 ± 10% and 90 ± 6% of the acetic acid-induced nociception, with ID₅₀ values of 51.3 and 50.2 mg/kg, respectively. In the glutamate test, eugenol (0.3-100 mg/kg, i.p.) reduced the response behavior by 62 ± 5% with an ID₅₀ of 5.6 mg/kg. In addition, the antinociceptive effect of eugenol (10 mg/kg, i.p.) in the glutamate test was prevented by the i.p. treatment for mice with naloxone. The pretreatment of mice with eugenol (10 mg/kg, i.p.) was able to inhibit the nociception induced by the intrathecal (i.t.) injection of glutamate (37 ± 9%), kainic (acid kainite) (41 ± 12%), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (55 ± 5%), and substance P (SP) (39 ± 8%). Furthermore, eugenol (10 mg/kg, i.p.) also inhibited biting induced by tumor necrosis factor alpha (TNF-α, 65 ± 8%). These results extend our current knowledge of eugenol and confirm that it promotes significant antinociception against different mouse models of acute pain. The mechanism of action appears to involve the modulation of the opioid system and glutamatergic receptors (i.e., kainate and AMPA), and the inhibition of TNF-α. Thus, eugenol could represent an important compound in the treatment for acute pain.

  17. Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide induced peritonitis

    Institute of Scientific and Technical Information of China (English)

    LIU Zhi-hai; MA Yue-feng; WU Jun-song; GAN Jian-xin; XU Shao-wen; JIANG Guan-yu

    2010-01-01

    Background The nervous system, through the vagus nerve and its neurotransmitter acetylcholine, can down-regulate the systemic inflammation in vivo, and recently, a role of brain cholinergic mechanisms in activating this cholinergic anti-inflammatory pathway has been indicated. Galanthamine is a cholinesterase inhibitor and one of the centrally acting cholinergic agents available in clinic. This study aimed to evaluate the effect of galanthamine on circulating tumor necrosis factor alpha (TNF-α) in rats with lipopolysaccharide-induced peritonitis and the possible role of the vagus nerve in the action of galanthamine.Methods Rat models of lipopolysaccharide-induced peritonitis and bilateral cervical vagotomy were produced. In the experiment 1, the rats were randomly divided into control group, peritonitis group, and peritonitis groups treated with three dosages of galanthamine. In the experiment 2, the rats were randomly divided into sham group, sham plus peritonitis group, sham plus peritonitis group treated with galanthamine, vagotomy plus peritonitis group, and vagotomy plus peritonitis group treated with galanthamine. The levels of plasma TNF-α were determined in every group. Results The level of circulating TNF-α was significantly increased in rats after intraperitoneal injection of endotoxin. Galanthamine treatment decreased the level of circulating TNF-α in rats with lipopolysaccharide-induced peritonitis, and there was significant difference compared with rats with lipopolysaccharide-induced peritonitis without treatment. The 3 mg/kg dosage of galanthamine had the most significant inhibition on circulating TNF-α level at all the three tested doses. Galanthamine obviously decreased the TNF-α level in rats with lipopolysaccharide-induced peritonitis with sham operation, but could not decrease the TNF-α level in rats with lipopolysaccharide-induced peritonitis with vagotomy. Conclusion Cholinesterase inhibitor galanthamine has an inhibitory effect on TNF

  18. Effects of Propyl Gallate on Adhesion of Polymorphonuclear Leukocytes to Human Endothelial Cells Induced by Tumor Necrosis Factor Alpha

    Institute of Scientific and Technical Information of China (English)

    JIANG Yue-rong; CHEN Ke-ji; XU Yong-gang; YANG Xiao-hong; YIN Hui-jun

    2009-01-01

    Objective: To investigate the effects of Prowl Gallate (PrG) on cellular adhesion between human umbilical vein endothelial cells (HUVEC) and polymorphonuclear leukocytes (PMN) as well as the expression of intercellular adhesion molecule-1 (ICAM-1, CD54) and E-selectin (CD62E) on the VEC surface. Methods: A human VEC inflammation model was induced by tumor necrosis factor alpha (TNF-α). VECs were pre-incubated with varying concentrations of PrG (0.001-5 mmol/L) or 1‰ DMSO (v:v) or 10 mmol/L acetylsalicylic acid (ASA) for 1 h, and then were stimulated with 10 ng/mL TNF-α for 6 h. Rose bengal vital staining method was used to measure the adherence rate of PMN to VEC, while flow cytometry was used to determine the expression of CD54 and CD62E on the VEC surface. Results: After 6 h of incubation with TNF-α, the adherence of PMN to HUVECs as well as the percentage of fluorescence-positive cells and mean fluorescence intensity (MFI) of surface CD54 and CD62E in HUVECs increased significantly (P0.05). ASA at 10 mmol/L had no obvious effect on the positive rate of CD62E and CD54. Conclusions: High concentrations of PrG (0.1-5 mmol/L) exert its inhibitory effect on cellular adherence of PMN to HUVECs, and its mechanism may be related to inhibiting surface expression of CD54 and CD62E in HUVECs. Its action concentration was lower than that of ASA.

  19. High plasma tumor necrosis factor (TNF)-alpha concentrations and a sepsis-like syndrome in patients undergoing hyperthermic isolated limb perfusion with recombinant TNF-alpha, interferon-gamma, and melphalan

    NARCIS (Netherlands)

    Zwaveling, JH; Maring, JK; Clarke, FL; vanGinkel, RJ; Limburg, PC; Hoekstra, HJ; Girbes, ARJ; Schraffordt Koops, H.

    1996-01-01

    Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreat ment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissu

  20. Antiproliferative action of tumor necrosis factor-alpha on MCF-7 breastcancer cells is associated with increased insulin-like growth factor binding protein-3 accumulation.

    Science.gov (United States)

    Rozen, F; Zhang, J; Pollak, M

    1998-10-01

    Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine involved in host response to neoplasia. TNF-alpha has been shown to inhibit proliferation and induce apoptosis of MCF-7 breast carcinoma cells. Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens involved in growth regulation of breast epithelial cells and are implicated in the pathophysiology of breast cancer. Their bioactivity is strongly influenced by specific IGF-binding proteins (IGFBPs). We report that accumulation of IGFBP-3 in the conditioned media of MCF-7 cells is increased over control values in the presence of TNF-alpha. The increased IGFBP-3 accumulation induced by TNF-alpha is correlated with increased IGFBP-3 mRNA abundance. TNF-alpha also decreases IGF-I receptor levels in MCF-7 cells. Estradiol-stimulated MCF-7 cell proliferation is associated with reduced IGFBP-3 accumulation, and we show that TNF-alpha attenuation of estradiol-stimulated proliferation is associated with increased IGFBP-3 accumulation. Finally, we demonstrate that an IGFBP-3 antisense oligodeoxynucleotide antagonizes TNF-alpha-induced inhibition of cell proliferation and TNF-alpha-induced IGFBP-3 accumulation. These data strongly suggest that IGFBP-3 plays a role in modulation of breast cancer cell proliferation by TNF-alpha.

  1. Analysis and Quantitation of NF-[kappa]B Nuclear Translocation in Tumor Necrosis Factor Alpha (TNF-[alpha]) Activated Vascular Endothelial Cells

    Science.gov (United States)

    Fuseler, John W.; Merrill, Dana M.; Rogers, Jennifer A.; Grisham, Matthew B.; Wolf, Robert E.

    2006-07-01

    Nuclear factor kappa B (NF-[kappa]B) is a heterodimeric transcription factor typically composed of p50 and p65 subunits and is a pleiotropic regulator of various inflammatory and immune responses. In quiescent cells, p50/p65 dimers are sequestered in the cytoplasm bound to its inhibitors, the I-[kappa]Bs, which prevent entry into the nucleus. Following cellular stimulation, the I-[kappa]Bs are rapidly degraded, activating NF-[kappa]B. The active form of NF-[kappa]B rapidly translocates into the nucleus, binding to consensus sequences in the promoter/enhancer region of various genes, promoting their transcription. In human vascular endothelial cells activated with tumor necrosis factor-alpha, the activation and translocation of NF-[kappa]B is rapid, reaching maximal nuclear localization by 30 min. In this study, the appearance of NF-[kappa]B (p65 subunit, p65-NF-[kappa]B) in the nucleus visualized by immunofluorescence and quantified by morphometric image analysis (integrated optical density, IOD) is compared to the appearance of activated p65-NF-[kappa]B protein in the nucleus determined biochemically. The appearance of p65-NF-[kappa]B in the nucleus measured by fluorescence image analysis and biochemically express a linear correlation (R2 = 0.9477). These data suggest that localization and relative protein concentrations of NF-[kappa]B can be reliably determined from IOD measurements of the immunofluorescent labeled protein.

  2. Human immunodeficiency virus infection alters tumor necrosis factor alpha production via Toll-like receptor-dependent pathways in alveolar macrophages and U1 cells.

    Science.gov (United States)

    Nicol, Marlynne Q; Mathys, Jean-Marie; Pereira, Albertina; Ollington, Kevin; Ieong, Michael H; Skolnik, Paul R

    2008-08-01

    Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-alpha) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-alpha/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-alpha is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-alpha production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam(3)Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-alpha in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-alpha production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that

  3. The expression of tumor necrosis factor-alpha, its receptors and steroidogenic acute regulatory protein during corpus luteum regression

    Directory of Open Access Journals (Sweden)

    Arfuso Frank

    2008-11-01

    Full Text Available Abstract Background Corpus luteum (CL regression is known to occur as two parts; functional regression when steroidogenesis declines and structural regression when apoptosis is induced. Previous studies suggest this process occurs by the production of luteolytic factors, such as tumour necrosis factor-alpha (TNF-alpha. Methods We examined TNF-alpha, TNF-alpha receptors (TNFR1 and 2 and steroidogenic acute regulatory (StAR protein expression during CL regression in albino Wistar rats. CL from Days 16 and 22 of pregnancy and Day 3 post-partum were examined, in addition CL from Day 16 of pregnancy were cultured in vitro to induce apoptosis. mRNA was quantitated by kinetic RT-PCR and protein expression examined by immunohistochemistry and Western blot analyses. Results TNF-alpha mRNA increased on Day 3 post-partum. TNFR were immunolocalized to luteal cells, and an increase in TNFR2 mRNA observed on Day 3 post-partum whilst no change was detected in TNFR1 mRNA relative to Day 16. StAR protein decreased on Day 3 post-partum and following trophic withdrawal but no change was observed following exogenous TNF-alpha treatment. StAR mRNA decreased on Day 3 post-partum; however, it increased following trophic withdrawal and TNF-alpha treatment in vitro. Conclusion These results demonstrate the existence of TNFR1 and TNFR2 in rat CL and suggest the involvement of TNF-alpha in rat CL regression following parturition. Furthermore, decreased StAR expression over the same time points was consistent with the functional regression of the CL.

  4. Association of polymorphism of tumor necrosis factor-alpha gene promoter region with outcome of hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    Hong-Quan Li; Zhuo Li; Ying Liu; Jun-Hong Li; Jian-Qun Dong; Ji-Rong Gao; Chun-Yan Gou; Hui Li

    2005-01-01

    AIM: To determine whether -238G/A and -857C/T polymorphisms of tumor necrosis factor-alpha (TNF-α), gene promoter and hepatitis B (HB) viral genotypes were associated with outcomes of HBV infection.METHODS: A total of 244 HBV self-limited infected subjects, 208 asymptomatic carriers, and 443 chronic HB patients were recruited to conduct a case-control study.TNF-α -238G/A and -857C/T gene promoter polymorphisms were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and HBV genotypes were examined by nested PCR.RESULTS: The positive rate of HBV DNA in asymptomatic carrier group and chronic HB group was 46.6% and 49.9%,respectively. HBV genotype proportion among the asymptomatic carriers was 2.1% for genotype A, 25.8% for genotype B, 68.0% for genotype C, and 4.1% for genotype B+C mixed infection, and 0.9% for genotype A,21.7% for genotype B, 71.5% for genotype C, 5.9% for genotype B+C mixed infection in chronic HB group. There was no significant difference in genotype distribution between the asymptomatic carrier group and chronic HB group (x2 = 1.66, P = 0.647). The frequency of -238GG genotype in self-limited group was 95.1%, significantly higher than 90.7% in chronic HB group and 89.0% in asymptomatic carrier group (P = 0.041 and P = 0.016,respectively).The frequency of TNF-α-857 CC in chronic HB group was 79.7%, significantly higher than 64.4% in asymptomatic carrier group and 70.9% in self-limited group (P<0.001 and P = 0.023, respectively). A multiple logistic regression analysis revealed that TNF-α-238GA and -857CC were independently associated with chronic HB after gender and age were adjusted.CONCLUSION: TNF-α promoter variants are likely to play a substantial role in the outcome of HBV infection.

  5. Effects of erythropoietin on the expression of tumor necrosis factor-alpha and Bax after facial nerve axotomy in rats

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Shengyu Lü; Ziying Yu; Ming Bi; Bin Sun

    2011-01-01

    This study sought to evaluate the effect of high-dose erythropoietin (EPO; 5 000 IU/kg) on the expression of tumor necrosis factor-alpha (TNF-α) and Bax in the facial nucleus after facial nerve transection in rats. A total of 42 Wistar rats of both genders were used in this study, and 40 rats were randomly divided into 2 groups: EPO group and model group. The EPO group was treated with EPO once a day for 5 days at a dose of 5 000 IU/kg body weight. The model group was treated with saline of the same amount. At day 3 after EPO (or saline) treatment, the right facial nerves of the 40 rats were transected at the level of the stylomastoid foramen, with the left sides untreated. The remaining 2 rats that did not undergo axotomy served as the control group. The surviving motor neurons in operated rats were counted in coronal paraffin sections of the facial nucleus. The expression of TNF-α and Bax in the facial nucleus was detected by immunohistochemical staining at days 3, 7, 14, 21, and 28 after axotomy. At days 14, 21, and 28 after facial nerve axotomy, a significantly greater proportion of facial motor neurons survived in the EPO group than in the model group. After axotomy, the expression of TNF-α and Bax increased in motor neurons in both the EPO and the model groups. TNF-α expression reached its peak level at day 14 after axotomy, while Bax expression reached its peak level at day 21. TNF-α expression was much lower in the EPO group than in the model group at all time points. No significant difference in Bax expression was found between the EPO and the model groups. These results indicate that high-dose EPO treatment attenuates the increase in TNF-α expression in the facial nucleus and reduces the loss of motor neurons after facial nerve transection in rats. However, high-dose EPO treatment has little effect on Bax expression.

  6. Human macrophage inflammatory protein-3alpha/CCL20/LARC/Exodus/SCYA20 is transcriptionally upregulated by tumor necrosis factor-alpha via a non-standard NF-kappaB site.

    Science.gov (United States)

    Harant, H; Eldershaw, S A; Lindley, I J

    2001-12-14

    The 5'-flanking sequences of the human macrophage inflammatory protein-3alpha/CCL20 gene were cloned and transfected into G-361 human melanoma cells in a luciferase reporter construct. Tumor necrosis factor-alpha (TNF-alpha) treatment stimulated luciferase expression, and promoter truncations demonstrated that TNF-alpha inducibility is conferred by a region between nt -111 and -77, which contains a non-standard nuclear factor-kappaB (NF-kappaB) binding site. The requirement for NF-kappaB was demonstrated as follows: (i) mutations in this NF-kappaB site abrogated TNF-alpha responsiveness; (ii) TNF-alpha activated a construct containing two copies of the CCL20 NF-kappaB binding site; (iii) overexpression of NF-kappaB p65 activated the CCL20 promoter; (iv) NF-kappaB from nuclear extracts of TNF-alpha-stimulated cells bound specifically to this NF-kappaB site.

  7. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys

    2009-01-01

    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

  8. The repeatability of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein in COPD patients over one year

    DEFF Research Database (Denmark)

    Kolsum, Umme; Roy, Kay; Starkey, Cerys

    2009-01-01

    BACKGROUND: Many of the systemic manifestations of chronic obstructive pulmonary disease (COPD) are mediated through increased systemic levels of inflammatory proteins. We assessed the long term repeatability of Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein......(i)) and the Bland-Altman method. Pearson correlations were used to determine the relationships between the systemic markers at both visits. RESULTS: There was moderate repeatability with a very high degree of statistical significance (p...... (CRP) over one year and examined the relationships between these systemic markers in COPD. METHODS: Fifty-eight stable COPD patients completed a baseline and one-year visit. Serum IL-6, plasma CRP, and plasma TNF-alpha were measured. Repeatability was expressed by intraclass correlation coefficient (R...

  9. The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor alpha in monocytes

    DEFF Research Database (Denmark)

    Benfield, T L; Lundgren, Bettina; Levine, S J

    1997-01-01

    Recent studies suggest that interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) may play a central role in host defense and pathogenesis during Pneumocystis carinii pneumonia. In order to investigate whether the major surface antigen (MSG) of human P. carinii is capable of eliciting...... the release of IL-8 and TNF-alpha, human monocytes were cultured in the presence of purified MSG. MSG-stimulated cells released significant amounts of IL-8 within 4 h, and at 20 h, cells stimulated with MSG released 45.5 +/- 9.3 ng of IL-8/ml versus 3.7 +/- 1.1 ng/ml for control cultures (P = 0...... with 0.2 to 5 microg of MSG/ml (P

  10. Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha.

    Science.gov (United States)

    Kim, Hyon Jong; Chang, Eun-Ju; Kim, Hyun-Man; Lee, Seung Bok; Kim, Hyun-Duck; Su Kim, Ghi; Kim, Hong-Hee

    2006-05-01

    The relationship between oxidative stress and bone mineral density or osteoporosis has recently been reported. As bone loss occurring in osteoporosis and inflammatory diseases is primarily due to increases in osteoclast number, reactive oxygen species (ROS) may be relevant to osteoclast differentiation, which requires receptor activator of nuclear factor-kappaB ligand (RANKL). Tumor necrosis factor-alpha (TNF-alpha) frequently present in inflammatory conditions has a profound synergy with RANKL in osteoclastogenesis. In this study, we investigated the effects of alpha-lipoic acid (alpha-LA), a strong antioxidant clinically used for some time, on osteoclast differentiation and bone resorption. At concentrations showing no growth inhibition, alpha-LA potently suppressed osteoclastogenesis from bone marrow-derived precursor cells driven either by a high-dose RANKL alone or by a low-dose RANKL plus TNF-alpha (RANKL/TNF-alpha). alpha-LA abolished ROS elevation by RANKL or RANKL/TNF-alpha and inhibited NF-kappaB activation in osteoclast precursor cells. Specifically, alpha-LA reduced DNA binding of NF-kappaB but did not inhibit IKK activation. Furthermore, alpha-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-alpha in a calvarial remodeling model. Therefore, our data provide evidence that ROS plays an important role in osteoclast differentiation through NF-kappaB regulation and the antioxidant alpha-lipoic acid has a therapeutic potential for bone erosive diseases.

  11. Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) associated with hypogammaglobulinemia and elevated serum tumor necrosis factor-alpha levels.

    Science.gov (United States)

    Edrees, Amr F; Kaplan, David L; Abdou, Nabih I

    2002-10-01

    Pyogenic aseptic arthritis, pyoderma gangrenosum, and cystic acne (PAPA) syndrome is an unusual triad that was recently mapped to a chromosome 15q mutation. We describe a patient from this kindred in whom hypogammaglobulinemia and elevated tumor necrosis factor-alpha serum levels were detected. The patient responded well to intravenous gammaglobulin and intra-articular corticosteroid therapy. Immune abnormalities can be found in PAPA syndrome and could be the consequence of the chromosomal abnormalities affecting candidate genes on this chromosome with subsequent abnormalities in cytokine or chemokine secretion. Rheumatologists should be alert for this syndrome. Correction of the immune abnormalities may be effective in controlling the disease manifestations.

  12. Effects of glucocorticoids and tumor necrosis factor-alpha inhibitors on both clinical and molecular parameters in patients with Takayasu arteritis

    Directory of Open Access Journals (Sweden)

    Raffaele Serra

    2014-01-01

    Full Text Available Objective: To explore the effect of sequential treatment with glucocorticoid and tumor necrosis factor-alpha inhibitors in patients with Takayasu arteritis (TA. Materials and Methods: In five patients with TA, the effects of the sequential treatment with prednisone for 5-7 months and then with adalimumab (ADA + methotrexate (MTX or infliximab + MTX, or with ADA only, for 12 months on both clinical and laboratory findings were evaluated. Results: All treatments improved both symptoms and laboratory parameters without the development of side-effects. Conclusions: It was hypothesized that MMP-9 and neutrophil gelatinase-associated lipocalin could be markers of the response to the treatments.

  13. Tumor necrosis factor-{alpha} enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Song, Kai; Zhu, Fei; Zhang, Han-zhong [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); Shang, Zheng-jun, E-mail: shangzhengjun@hotmail.com [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST), Key Laboratory for Oral Biomedicine Ministry of Education, Wuhan University, Wuhan (China); First Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan (China)

    2012-08-15

    Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-{alpha}-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer-endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-{alpha} could enhance cancer-endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer-endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis. -- Highlights: Black-Right-Pointing-Pointer Spontaneous oral cancer-endothelial cell fusion. Black-Right-Pointing-Pointer TNF-{alpha} enhanced cell fusions. Black-Right-Pointing-Pointer VCAM-1/VLA-4 expressed in oral cancer. Black-Right-Pointing-Pointer TNF-{alpha} increased expression of VCAM-1 on endothelial cells. Black

  14. Tumor necrosis factor alpha as a marker of systemic and local inflammation in “healthy” smokers

    Directory of Open Access Journals (Sweden)

    Juan M Diez-Pina

    2009-02-01

    Full Text Available Juan M Diez-Pina1, María J Fernandez-Aceñero3, María J Llorente-Alonso2, Salvador Diaz-Lobato4, Sagrario Mayoralas1, Asuncion Florez11Department of Pneumology; 2Department of Biochemistry, Hospital de Móstoles, Móstoles, Madrid, Spain; 3Department of Pathology, Fundacíon Jiménez-Díaz, Madrid, Spain; 4Department of Pneumology, Hospital Ramón y Cajal, Madrid, SpainBackground: Tobacco smoking induces a local and systemic inflammatory reaction and also a decline in pulmonary function. There are some novel noninvasive methods to measure the degree of inflammatory bronchial reaction, including the exhaled breath condensate (EBC in which several inflammatory markers can be measured, including tumor necrosis factor alpha (TNF-α. There is a clear clinical need to develop methods that allow early detection of smokers at risk of losing pulmonary function.Objectives: The aims of the present study are: 1 to show that smokers show higher levels of TNF-α both in serum and EBC; 2 to analyze the possible influence of gender, age, and weight on this parameter; and 3 to determine a possible association between smoking and pulmonary function parameters and TNF-α levels.Material and methods: We have prospectively analyzed two cohorts of smokers and nonsmokers subjects without any chronic or acute disease (within eight weeks of study initiation. We have performed pulmonary function tests with bronchodilators and also collected EBC and blood samples before smoking cessation. Statistical analysis was performed with SPSS 11.0 for Windows Statistical Package.Results: The study has enrolled 17 patients (8 smokers, 50% of whom were females. Mean age was 38.59 years old (standard deviation, 7.4. The mean number of cigarettes smoked in the smoker group was 26.14 (11.29 cigarettes/day and the mean age when tobacco first began was 15.14 (2.04 years. We have not been able to show any significant differences in TNF-α levels according to age or weight. For the whole

  15. Beneficial effects of post-transfusional hepatitis in acute myelogenous leukemia may be mediated by lipopolysaccharides, tumor necrosis factor alpha and interferon gamma.

    Science.gov (United States)

    Treon, S P; Broitman, S A

    1992-10-01

    Post-transfusional hepatitis is often a complication in patients with acute myelogenous leukemia (AML) in whom survival is paradoxically prolonged. The etiology is unknown. In previous studies, we showed that impaired hepatic endotoxin (lipopolysaccharide, LPS) clearance in patients with acute viral hepatitis A, B, or C versus controls results in endotoxemia and tumor necrosis factor alpha (TNF-alpha) release. TNF-alpha mediates anti-proliferative and differentiating effects in AML cell lines. Interferon-gamma (IFN-gamma) released in acute viral hepatitis, acts in synergy with TNF-alpha. HL60, KG1, and U937 AML cells treated 3, 6, and 9 days with physiologically attainable TNF-alpha (10 U/ml), IFN-gamma (100 U/ml) and LPS (10 ng/ml) levels, have significantly diminished viability and cell growth versus controls. Treatment of HL60 AML cells with LPS/TNF-alpha/IFN-gamma also resulted in significantly increased monocytic pathway differentiation not seen with KG1 or U937 AML cells. HL60 AML cells treated with TNF-alpha/IFN-gamma for 6 days released endogenous TNF-alpha (1.57 U/10(6) cells) upon LPS stimulation compared to less than 0.01 U/10(6) cells in non-LPS-stimulated TNF-alpha/IFN-gamma-treated cells or untreated cells (p less than 0.0001). Untreated HL60 AML cells co-cultured with HL60 cells pretreated for 6 days with TNF-alpha/IFN-gamma and then subjected to LPS stimulation had significantly diminished cell growth compared to controls (p less than 0.0001). This effect could be reversed with anti-TNF-alpha antibody, supporting the concept that endogenous TNF-alpha release by LPS/TNF-alpha/IFN-gamma treated HL60 AML cells may act by paracrine means to suppress growth of other AML cells. The beneficial effects of post-transfusional hepatitis in AML patients may be mediated via LPS/TNF-alpha/IFN-gamma-induced AML cell growth suppression and/or terminal differentiation in which AML cells participate by releasing TNF-alpha after being acted upon by LPS/TNF-alpha

  16. Mechanisms of tumor cell necrosis.

    Science.gov (United States)

    Proskuryakov, Sergey Y; Gabai, Vladimir L

    2010-01-01

    Until recently, necrosis, unlike apoptosis, was considered as passive and unregulated form of cell death. However, during the last decade a number of experimental data demonstrated that, except under extreme conditions, necrosis may be a well-regulated process activated by rather specific physiological and pathological stimuli. In this review, we consider mechanisms and the role of necrosis in tumor cells. It became recently clear that the major player in necrotic cascade is a protein kinase RIP1, which can be activated by number of stumuli including TNF, TRAIL, and LPS, oxidative stress, or DNA damage (via poly-ADP-ribose polymerase). RIP1 kinase directly (or indirectly via another kinase JNK) transduces signal to mitochondria and causes specific damage (mitochondrial permeability transition). Mitochondrial collapse activates various proteases (e.g., calpains, cathepsin) and phospholipases, and eventually leads to plasma membrane destruction, a hallmark of necrotic cell death. Necrosis, in contrast to apoptosis, usually evokes powerful inflammatory response, which may participate in tumor regression during anticancer therapy. On the other hand, excessive spontaneous necrosis during tumor development may lead to more aggressive tumors due to stimulatory role of necrosis-induced inflammation on their growth.

  17. Tumor Necrosis Factor-Alpha and the ERK Pathway Drive Chemerin Expression in Response to Hypoxia in Cultured Human Coronary Artery Endothelial Cells

    Science.gov (United States)

    Chua, Su-Kiat; Shyu, Kou-Gi; Lin, Yuh-Feng; Lo, Huey-Ming; Wang, Bao-Wei

    2016-01-01

    Background Chemerin, a novel adipokine, plays a role in the inflammation status of vascular endothelial cells. Hypoxia causes endothelial-cell proliferation, migration, and angiogenesis. This study was aimed at evaluating the protein and mRNA expression of chemerin after exposure of human coronary artery endothelial cells (HCAECs) to hypoxia. Methods and Results Cultured HCAECs underwent hypoxia for different time points. Chemerin protein levels increased after 4 h of hypoxia at 2.5% O2, with a peak of expression of tumor necrosis factor-alpha (TNF-alpha) at 1 h. Both hypoxia and exogenously added TNF-alpha during normoxia stimulated chemerin expression, whereas an ERK inhibitor (PD98059), ERK small interfering RNA (siRNA), or an anti-TNF-alpha antibody attenuated the chemerin upregulation induced by hypoxia. A gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between the chemerin promoter and transcription factor SP1. A luciferase assay confirmed an increase in transcriptional activity of SP1 on the chemerin promoter during hypoxia. Hypoxia significantly increased the tube formation and migration of HCAECs, whereas PD98059, the anti-TNF-alpha antibody, and chemerin siRNA each attenuated these effects. Conclusion Hypoxia activates chemerin expression in cultured HCAECs. Hypoxia-induced chemerin expression is mediated by TNF-alpha and at least in part by the ERK pathway. Chemerin increases early processes of angiogenesis by HCAECs after hypoxic treatment. PMID:27792771

  18. Effects of tumor necrosis factor-alpha and interferon-gamma on expressions of matrix metalloproteinase-2 and -9 in human bladder cancer cells.

    Science.gov (United States)

    Shin, K Y; Moon, H S; Park, H Y; Lee, T Y; Woo, Y N; Kim, H J; Lee, S J; Kong, G

    2000-10-31

    We have investigated the effects of tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), the potent Bacillus Calmette-Guerin (BCG)-induced cytokines on the production of MMP-2, MMP-9, TIMP-1, TIMP-2 and MT1-MMP in high grade human bladder cancer cell lines, T-24, J-82 and HT-1376 cell lines. MMP-2 expression and activity were decreased in T-24 cells treated with both cytokines in a dose dependent manner. However, J-82 cells treated with TNF-alpha and INF-gamma revealed dose dependent increases of MMP-9 expression and activity with similar baseline expression and activity of MMP-2. HT-1376 cells after exposure to TNF-alpha only enhanced the expression and activity of MMP-9. These results indicate that TNF-alpha and INF-gamma could regulate the production of MMP-2 or MMP-9 on bladder cancer cells and their patterns of regulation are cell specific. Furthermore, this diverse response of bladder cancer cells to TNF-alpha and INF-gamma suggests that BCG immunotherapy may enhance the invasiveness of bladder cancer in certain conditions with induction of MMPs.

  19. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Chao, C C; Hu, S; Ehrlich, L; Peterson, P K

    1995-12-01

    The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases; however, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1beta and TNF-alpha in combination caused marked neuronal injury. Brain cell cultures treated with IL-1beta plus TNF-alpha generated substantial amounts of NO. Blockade of NO production with a NO synthase inhibitor was accompanied by a marked reduction (about 45%) of neuronal injury, suggesting that NO production by astrocytes plays a role in cytokine-induced neurotoxicity. Addition of N-methly-D-aspartate (NMDA) receptor antagonists to brain cell cultures also blocked IL-1beta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the involvement of NMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1beta plus TNF-alpha was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity. These in vitro findings suggest that agents which suppress NO production or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases.

  20. Daily injection of tumor necrosis factor-{alpha} increases hepatic triglycerides and alters transcript abundance of metabolic genes in lactating dairy cattle.

    Science.gov (United States)

    Bradford, Barry J; Mamedova, Laman K; Minton, J Ernest; Drouillard, James S; Johnson, Bradley J

    2009-08-01

    To determine whether inflammation can induce bovine fatty liver, we administered recombinant bovine tumor necrosis factor-alpha (rbTNF) to late-lactation Holstein cows. Cows (n = 5/treatment) were blocked by feed intake and parity and randomly assigned within block to control (CON; saline), rbTNF at 2 microg/(kg.d), or pair-fed control (saline, intake matched) treatments. Treatments were administered once daily by subcutaneous injection for 7 d. Plasma samples were collected daily for analysis of glucose and FFA and a liver biopsy was collected on d 7 for triglyceride (TG) and quantitative RT-PCR analyses. Data were analyzed using treatment contrasts to assess effects of tumor necrosis factor-alpha (TNFalpha) and decreased feed intake. By d 7, feed intake of both rbTNF and pair-fed cows was approximately 15% less than CON (P carnitine palmitoyltransferase 1 transcript abundance tended to be lower (P = 0.09) and transcript abundance of fatty acid translocase and 1-acyl-glycerol-3-phosphate acyltransferase was higher (both P < 0.05) after rbTNF treatment, consistent with increased FFA uptake and storage as TG. Transcript abundance of glucose-6-phosphatase (P < 0.05) and phosphoenolpyruvate carboxykinase 1 (P = 0.09), genes important for gluconeogenesis, was lower for rbTNF-treated cows. These findings indicate that TNFalpha promotes liver TG accumulation and suggest that inflammatory pathways may also be responsible for decreased glucose production in cows with fatty liver.

  1. Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis.

    Science.gov (United States)

    Babbar, Naveen; Casero, Robert A

    2006-12-01

    Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-alpha (TNF-alpha) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-alpha exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-alpha-treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H(2)O(2). Inhibition of TNF-alpha-induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H(2)O(2) by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers.

  2. Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population.

    Science.gov (United States)

    Jiménez-Morales, Silvia; Velázquez-Cruz, Rafael; Ramírez-Bello, Julián; Bonilla-González, Edmundo; Romero-Hidalgo, Sandra; Escamilla-Guerrero, Guillermo; Cuevas, Francisco; Espinosa-Rosales, Francisco; Martínez-Aguilar, Nora Ernestina; Gómez-Vera, Javier; Baca, Vicente; Orozco, Lorena

    2009-04-01

    There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha (TNF-alpha) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF-alpha promoter region have been associated with disease susceptibility and severity. We investigated whether -308G/A and -238G/A TNF-alpha polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF-alpha polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF-alpha-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients (p = 0.002 and p = 0.0086), and 6.7% of SLE patients (p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the -308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF-alpha -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-alpha gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.

  3. Pathway-specific profiling identifies the NF-kappa B-dependent tumor necrosis factor alpha-regulated genes in epidermal keratinocytes.

    Science.gov (United States)

    Banno, Tomohiro; Gazel, Alix; Blumenberg, Miroslav

    2005-05-13

    Identification of tumor necrosis factor alpha (TNF alpha) as the key agent in inflammatory disorders led to new therapies specifically targeting TNF alpha and avoiding many side effects of earlier anti-inflammatory drugs. However, because of the wide spectrum of systems affected by TNF alpha, drugs targeting TNF alpha have a potential risk of delaying wound healing, secondary infections, and cancer. Indeed, increased risks of tuberculosis and carcinogenesis have been reported as side effects after anti-TNF alpha therapy. TNF alpha regulates many processes (e.g. immune response, cell cycle, and apoptosis) through several signal transduction pathways that convey the TNF alpha signals to the nucleus. Hypothesizing that specific TNF alpha-dependent pathways control specific processes and that inhibition of a specific pathway may yield even more precisely targeted therapies, we used oligonucleotide microarrays and parthenolide, an NF-kappa B-specific inhibitor, to identify the NF-kappa B-dependent set of the TNF alpha-regulated genes in human epidermal keratinocytes. Expression of approximately 40% of all TNF alpha-regulated genes depends on NF-kappa B; 17% are regulated early (1-4 h post-treatment), and 23% are regulated late (24-48 h). Cytokines and apoptosis-related and cornification proteins belong to the "early" NF-kappa B-dependent group, and antigen presentation proteins belong to the "late" group, whereas most cell cycle, RNA-processing, and metabolic enzymes are not NF-kappa B-dependent. Therefore, inflammation, immunomodulation, apoptosis, and differentiation are on the NF-kappa B pathway, and cell cycle, metabolism, and RNA processing are not. Most early genes contain consensus NF-kappaB binding sites in their promoter DNA and are, presumably, directly regulated by NF-kappa B, except, curiously, the cornification markers. Using siRNA silencing, we identified cFLIP/CFLAR as an essential NF-kappa B-dependent antiapoptotic gene. The results confirm our

  4. Tumor necrosis factor-alpha induced expression of matrix metalloproteinase-9 through p21-activated Kinase-1

    Directory of Open Access Journals (Sweden)

    Garner Warren

    2009-03-01

    Full Text Available Abstract Background Expressed in embryonic development, matrix metalloprotein-9 (MMP-9 is absent in most of developed adult tissues, but recurs in inflammation during tissue injury, wound healing, tumor formation and metastasis. Expression of MMP-9 is tightly controlled by extracellular cues including pro-inflammatory cytokines and extracellular matrix (ECM. While the pathologic functions of MMP-9 are evident, the intracellular signaling pathways to control its expression are not fully understood. In this study we investigated mechanism of cytokine induced MMP-9 with particular emphasis on the role of p21-activated-kinase-1 (PAK1 and the down stream signaling. Results In response to TNF-alpha or IL-1alpha, PAK1 was promptly activated, as characterized by a sequential phosphorylation, initiated at threonine-212 followed by at threonine-423 in the activation loop of the kinase, in human skin keratinocytes, dermal fibroblasts, and rat hepatic stellate cells. Ectopic expression of PAK1 variants, but not p38 MAP kinase, impaired the TNF-alpha-induced MMP-9 expression, while other MMPs such as MMP-2, -3 and -14 were not affected. Activation of Jun N-terminal kinase (JNK and NF-kappaB has been demonstrated to be essential for MMP-9 expression. Expression of inactive PAK1 variants impaired JNK but not NF-kappaB activation, which consequently suppressed the 5'-promoter activities of the MMP-9 gene. After the cytokine-induced phosphorylation, both ectopically expressed and endogenous PAK1 proteins were promptly accumulated even in the condition of suppressing protein synthesis, suggesting the PAK1 protein is stabilized upon TNF-alpha stimulation. Stabilization of PAK1 protein by TNF-alpha treatment is independent of the kinase catalytic activity and p21 GTPase binding capacities. In contrast to epithelial cells, mesenchymal cells require 3-dimensional type-I collagen in response to TNF-alpha to massively express MMP-9. The collagen effect is mediated, in

  5. Suppressive effects of antimycotics on tumor necrosis factor-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes.

    Science.gov (United States)

    Kanda, Naoko; Watanabe, Shinichi

    2006-08-14

    Antimycotic agents are reported to improve cutaneous symptoms of atopic dermatitis or psoriasis vulgaris. Keratinocytes in these lesions excessively produce chemokines, CCL27, CCL2, or CCL5 which trigger inflammatory infiltrates. Tumor necrosis factor-alpha (TNF-alpha) induces production of these chemokines via activating nuclear factor-kappaB (NF-kappaB). We examined in vitro effects of antimycotics on TNF-alpha-induced CCL27, CCL2, and CCL5 production in human keratinocytes. Antimycotics ketoconazole and terbinafine hydrochloride suppressed TNF-alpha-induced CCL27, CCL2, and CCL5 secretion and mRNA expression in keratinocytes in parallel to the inhibition of NF-kappaB activity while fluconazole was ineffective. Anti-prostaglandin E2 (PGE2) antiserum or antisense oligonucleotides against PGE2 receptor EP2 or EP3 abrogated inhibitory effects of ketoconazole and terbinafine hydrochloride on TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production, indicating the involvement of endogenous PGE2 in the inhibitory effects. Prostaglandin H2, a precursor of PGE2 can be converted to thromboxane A2. Ketoconazole, terbinafine hydrochloride and thromboxane A2 synthase (EC 5.3.99.5) inhibitor, carboxyheptyl imidazole increased PGE2 release from keratinocytes and reduced that of thromboxane B2, a stable metabolite of thromboxane A2. Carboxyheptyl imidazole also suppressed TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production. These results suggest that ketoconazole and terbinafine hydrochloride may suppress TNF-alpha-induced NF-kappaB activity and CCL27, CCL2, and CCL5 production by increasing PGE2 release from keratinocytes. These antimycotics may suppress thromboxane A2 synthesis and redirect the conversion of PGH2 toward PGE2. These antimycotics may alleviate inflammatory infiltration in atopic dermatitis or psoriasis vulgaris by suppressing chemokine production.

  6. Dose effect of tumor necrosis factor-alpha on in vitro osteogenic differentiation of mesenchymal stem cells on biodegradable polymeric microfiber scaffolds.

    Science.gov (United States)

    Mountziaris, Paschalia M; Tzouanas, Stephanie N; Mikos, Antonios G

    2010-03-01

    This study presents a first step in the development of a bone tissue engineering strategy to trigger enhanced osteogenesis by modulating inflammation. This work focused on characterizing the effects of the concentration of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), on osteogenic differentiation of mesenchymal stem cells (MSCs) grown in a 3D culture system. MSC osteogenic differentiation is typically achieved in vitro through a combination of osteogenic supplements that include the anti-inflammatory corticosteroid dexamethasone. Although simple, the use of dexamethasone is not clinically realistic, and also hampers in vitro studies of the role of inflammatory mediators in wound healing. In this study, MSCs were pre-treated with dexamethasone to induce osteogenic differentiation, and then cultured in biodegradable electrospun poly(epsilon-caprolactone) (PCL) scaffolds, which supported continued MSC osteogenic differentiation in the absence of dexamethasone. Continuous delivery of 0.1 ng/mL of recombinant rat TNF-alpha suppressed osteogenic differentiation of rat MSCs over 16 days, which was likely the result of residual dexamethasone antagonizing TNF-alpha signaling. Continuous delivery of a higher dose, 5 ng/mL TNF-alpha, stimulated osteogenic differentiation for a few days, and 50 ng/mL TNF-alpha resulted in significant mineralized matrix deposition over the course of the study. These findings suggest that the pro-inflammatory cytokine TNF-alpha stimulates osteogenic differentiation of MSCs, an effect that can be blocked by the presence of anti-inflammatory agents like dexamethasone, with significant implications on the interplay between inflammation and tissue regeneration.

  7. Effects of salidroside pretreatment on expression of tumor necrosis factor-alpha and permeability of blood brain barrier in rat model of focal cerebralischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Tian Han

    2013-01-01

    Objective:To observe changes in expression of tumor necrosis factor(TNF)-alpha and permeability of blood brain barrier after salidroside pretreatment in rats with injury induced by focal cerebralischemia-reperfusion.Methods:Forty-five maleSD rats were randomly divided into three groups(n=15): control group, ischemia-reperfusion(IR) model group, and salidroside pretreatment group.Before theIR model establishment, the rats in the salidroside pretreatment group were intraperitoneally administered with salidroside at a dose of24 mg/(kg•d) for7 d.After30 min post the last administration, theIR model was induced by occlusion of middle cerebral artery with a filament.After24 h post the operation, the water content andEvens blue content in the ischemia cerebral hemisphere were determined, and the level of TNF-alpha mRNA was detected by the semi-quantitativeRT-PCR.Results:Compared with theIR model group, the salidroside pretreatment group had significantly lower(P<0.05) water content andEvens blue content in the ischemia cerebral hemisphere and also had significantly lower(P<0.05) level of TNF-alpha in the ischemic cerebral cortex tissue.Conclusions:The salidroside pretreatment alleviated the focal cerebralischemia-reperfusion injury in the rat model, possibly by decreasing the permeability of blood brain barrier, attenuating brain edema and reducingTNF-alpha expression.

  8. In vitro production of tumor necrosis factor-alpha by human monocytes stimulated with lipopolysaccharide is positively correlated with increased blood monocytes after exposure to a swine barn.

    Science.gov (United States)

    Willson, P J; Khozani, T Talaei; Juurlink, B H J; Senthilselvan, A; Rennie, D C; Gerdts, V; Gawaziuk, J; Schneberger, D; Burch, Lauranell H; Dosman, J A

    2008-01-01

    Recently there has been interest in the air quality in and around intensive livestock production facilities, such as modern swine production barns, where agricultural workers and surrounding residents may be exposed to elevated levels of organic dusts. The health effects of these exposures are not completely understood. The study that is reported here is a component of a larger investigation of the relationships among the acute effects of high-concentration endotoxin exposure (swine barn dust), polymorphisms in the TLR4 gene, and respiratory outcomes following exposure to swine confinement buildings. The relationships among a mediator of acute lung inflammation, tumor necrosis factor alpha (TNF-alpha), and clinical responses to acute swine barn exposure were characterized. Analysis of the results showed that in vitro stimulation of human monocytes with as little as 1 ng/ml of lipopolysaccharide (LPS) produced a significant increase in the monocytes that produced TNF-alpha. Although the proportion of TNF-alpha-positive monocytes after in vitro stimulation with 1 ng/ml of LPS was not associated with gender or TLR4 genotype, it was positively associated with the concentration of monocytes in blood after barn exposure. Thus, these two responses to different forms of LPS exposure are significantly correlated, and more responsive monocytes in vitro indicate a forthcoming relative monocytosis, post barn exposure, which may initiate a cascade of chronic inflammation.

  9. Evaluation of accuracy and uncertainty of ELISA assays for the determination of interleukin-4, interleukin-5, interferon-gamma and tumor necrosis factor-alpha

    DEFF Research Database (Denmark)

    Borg, Lone; Kristiansen, Jesper; Christensen, Jytte M

    2002-01-01

    . However, models for establishing the traceability and uncertainty of immunoassay results are lacking. Sandwich enzyme-linked immunosorbent assays (ELISAs) were developed for determination of the human cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-y (IFN-gamma) and tumor necrosis factor......-alpha (TNF-alpha). The accuracy of each of the assays was evaluated in the ranges of 1-15 microg/l (IL-4), 0.001-1 microg/l (IL-5), 0.5-2.5 microg/l (IFN-T) and 0.14-2.2 microg/l (TNF-alpha). Other evaluated performance characteristics were the limit of detection (LOD), immunological specificity......) of the assessed ELISAs was found to be in the range of 11-18%, except for IL-5 where RSDA increased at decreasing concentrations. The LOD was 0.12 microg/l, 0.0077 microg/l, 0.0069 microg/l and 0.0063 microg/l for IL-4, IL-5, IFN-gamma and TNF-alpha, respectively. Traceability to the WHO IS was established...

  10. The major surface glycoprotein of Pneumocystis carinii induces release and gene expression of interleukin-8 and tumor necrosis factor alpha in monocytes

    DEFF Research Database (Denmark)

    Benfield, T L; Lundgren, Bettina; Levine, S J;

    1997-01-01

    with 0.2 to 5 microg of MSG/ml (P TNF-alpha from MSG-stimulated monocytes at 20 h was inhibited by 60 and 86%, respectively, after coincubation with soluble yeast mannan (P = 0.01). With an RNase protection assay, increases in steady-state mRNA levels for IL-8 and TNF......Recent studies suggest that interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) may play a central role in host defense and pathogenesis during Pneumocystis carinii pneumonia. In order to investigate whether the major surface antigen (MSG) of human P. carinii is capable of eliciting...... the release of IL-8 and TNF-alpha, human monocytes were cultured in the presence of purified MSG. MSG-stimulated cells released significant amounts of IL-8 within 4 h, and at 20 h, cells stimulated with MSG released 45.5 +/- 9.3 ng of IL-8/ml versus 3.7 +/- 1.1 ng/ml for control cultures (P = 0...

  11. Effects of transforming growth factor beta, tumor necrosis factor alpha, interferon gamma and LIF-HILDA on the proliferation of acute myeloid leukemia cells.

    Science.gov (United States)

    Kerangueven, F; Sempere, C; Tabilio, A; Mannoni, P

    1990-01-01

    A group of polypeptide factors that regulate cell growth and differentiation has been tested for their biological activities on the growth and differentiation of leukemic cells isolated from patients with Acute Myeloid Leukemias (AML). The effects of Transforming Growth Factor beta 1 (TGF beta), Tumor Necrosis Factor alpha (TNF alpha), Interferon gamma (IFN gamma) and LIF-HILDA were compared on leukemic cells cultured in vitro for seven days. Spontaneously growing leukemic cells were selected in order to study either inhibition or enhancement of proliferation induced by these factors. Only TGF beta 1 was found to induce a clear inhibition of leukemic proliferation in all cases tested. Recombinant TNF alpha and IFN gamma were found to induce either inhibition or enhancement of the proliferation on separate specimens. Under the conditions of culture, it was not possible to document any effect of LIF-HILDA. Cell differentiation and cell maturation were documented studying the modulation of cell surface antigens. TGF beta did not modify antigen expression on the cells surviving after 3 days in culture. Both TNF alpha and IFN gamma were found to enhance the expression of adhesion molecules and to a lesser extent, the expression of some lineage associated antigens. No effect of LIF-HILDA on antigen modulation was documented in the cases tested. These data confirm that TGF beta is by itself a potent inhibitor of the myeloid leukemia cells proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Experimental study on inhibitory effect of niacinamide on tumor necrosis factor-alpha-induced matrix degradation of annulus fibrous tissue in vitro.

    Science.gov (United States)

    Xu, Runbing; Shao, Zengwu; Xiong, Liming

    2008-10-01

    The inhibitory effect of niacinamide on tumor necrosis factor-alpha (TNF-alpha) induced annulus fibrous (AF) degradation was assessed, and the mechanism of the inhibition was investigated. Chiba's intervertebral disc (IVD) culture model was established. Forty-eight IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups (12 IVDs in each group), and various concentrations of niacinamide and TNF-alpha were added to the medium for intervention: negative control group, niacinamide control group (0.5 mg/mL niacinamide), degeneration group (10 ng/mL TNF-alpha), and treatment group (0.5 mg/mL niacinamide and 10 ng/mL TNF-alpha). After one week's culture, AFs were collected for glycosaminoglycan (GS) content measurement, safranin O-fast green staining, and immunohistochemical staining for type I, II collagen and cysteine containing aspartate specific protease-3 (Caspase-3). It was found that the GS content in treatment group was increased by about 48% as compared with degeneration group (t=16.93, Pniacinamide control group (t=0.71, P=0.667). Safranine O-fast green staining exhibited higher staining density and better histological structure of AF in the treatment group as compared with the degeneration group. Immunohistochemical staining for both Type I and II collagen demonstrated that lamellar structure and continuity of collagen in treatment group were better reserved than in degeneration group. Positive staining rate of Caspase-3 in AFs of negative control group, niacinamide control group, degeneration group and treatment group was 3.4%, 4.3%, 17.9% and 10.3% respectively. The positive rate in treatment group was significantly lower than in degeneration group (Pniacinamide could effectively alleviate TNF-alpha induced destruction and synthesis inhibition of matrix ingredients in AFs. The inhibition may be related with reduction of expression of Caspase-3. Thus, niacinamide is of potential for IVD degeneration clinical treatment.

  13. Macrophage-elicited osteoclastogenesis in response to bacterial stimulation requires Toll-like receptor 2-dependent tumor necrosis factor-alpha production.

    Science.gov (United States)

    Ukai, Takashi; Yumoto, Hiromichi; Gibson, Frank C; Genco, Caroline Attardo

    2008-02-01

    The receptor activator of NF-kappaB ligand (RANKL) and the proinflammatory cytokines are believed to play important roles in osteoclastogenesis. We recently reported that the innate immune recognition receptor, Toll-like receptor 2 (TLR2), is crucial for inflammatory bone loss in response to infection by Porphyromonas gingivalis, the primary organism associated with chronic inflammatory periodontal disease. However, the contribution of macrophage-expressed TLRs to osteoclastogenesis has not been defined. In this study, we defined a requirement for TLR2 in tumor necrosis factor-alpha (TNF-alpha)-elicited osteoclastogenesis in response to exposure to P. gingivalis. Culture supernatant (CS) fluids from P. gingivalis-stimulated macrophages induced bone marrow macrophage-derived osteoclastogenesis. This activity was dependent on TNF-alpha and occurred independently of RANKL, interleukin-1beta (IL-1beta), and IL-6. CS fluids from P. gingivalis-stimulated TLR2(-/-) macrophages failed to express TNF-alpha, and these fluids induced significantly less osteoclast formation compared with that of the wild-type or the TLR4(-/-) macrophages. In addition, P. gingivalis exposure induced up-regulation of TLR2 expression on the cell surface of macrophages, which was demonstrated to functionally react to reexposure to P. gingivalis, as measured by a further increase in TNF-alpha production. These results demonstrate that macrophage-dependent TLR2 signaling is crucial for TNF-alpha-dependent/RANKL-independent osteoclastogenesis in response to P. gingivalis infection. Furthermore, the ability of P. gingivalis to induce the cell surface expression of TLR2 may contribute to the chronic inflammatory state induced by this pathogen.

  14. Plasma Tumor Necrosis Factor-alpha (TNF-α) Levels Correlate with Disease Severity in Spastic Diplegia, Triplegia, and Quadriplegia in Children with Cerebral Palsy.

    Science.gov (United States)

    Wu, Jianxian; Li, Xueming

    2015-12-11

    BACKGROUND Inflammatory responses in utero and in neonates have been involved in the development of white matter lesions. This study aimed to investigate the role of tumor necrosis factor-alpha (TNF-α) in spastic cerebral palsy. MATERIAL AND METHODS Plasma TNF-α was measured by ELISA in 54 children with spastic cerebral palsy and 28 aged-matched controls. Both groups were split into age subgroups (1-3 vs. 4-12). Gross motor function and activities of daily living were assessed on enrollment and after 6 months of rehabilitation. RESULTS TNF-α was higher in patients with cerebral palsy than in controls in young (Pcerebral palsy had significantly higher TNF-α levels compared with older ones (Pcerebral palsy showed higher plasma levels of TNF-α than controls. In addition, pre-treatment TNF-α levels were correlated with the improvements after rehabilitation therapy.

  15. Signaling mechanisms in tumor necrosis factor alpha-induced death of microvascular endothelial cells of the corpus luteum

    Directory of Open Access Journals (Sweden)

    Rueda Bo R

    2003-02-01

    Full Text Available Abstract The microvasculature of the corpus luteum (CL, which comprises greater than 50% of the total number of cells in the CL, is thought to be the first structure to undergo degeneration via apoptosis during luteolysis. These studies compared the apoptotic potential of various cytokines (tumor necrosis factor α, TNFα; interferon gamma, IFNγ; soluble Fas ligand, sFasL, a FAS activating antibody (FasAb, and the luteolytic hormone prostaglandin F2α (PGF2α on CL-derived endothelial (CLENDO cells. Neither sFasL, FasAb nor PGF2α had any effect on CLENDO cell viability. Utilizing morphological and biochemical parameters it was evident that TNFα and IFNγ initiated apoptosis in long-term cultures. However, TNFα was the most potent stimulus for CLENDO cell apoptosis at early time points. Unlike many other studies described in non-reproductive cell types, TNFα induced apoptosis of CLENDO cells occurs in the absence of inhibitors of protein synthesis. TNFα-induced death is typically associated with acute activation of distinct intracellular signaling pathways (e.g. MAPK and sphingomyelin pathways. Treatment with TNFα for 5–30 min activated MAPKs (ERK, p38, and JNK, and increased ceramide accumulation. Ceramide, a product of sphingomyelin hydrolysis, can serve as an upstream activator of members of the MAPK family independently in numerous cell types, and is a well-established pro-apoptotic second messenger. Like TNFα, treatment of CLENDO cells with exogenous ceramide significantly induced endothelial apoptosis. Ceramide also activated the JNK pathway, but had no effect on ERK and p38 MAPKs. Pretreatment of CLENDO cells with glutathione (GSH, an intracellular reducing agent and known inhibitor of reactive oxygen species (ROS or TNFα-induced apoptosis, significantly attenuated TNFα-induced apoptosis. It is hypothesized that TNFα kills CLENDO cells through elevation of reactive oxygen species, and intracellular signals that promote

  16. High-volume hemofiltration reduces the expression of myocardial tumor necrosis factor-alpha in septic shock pigs.

    Science.gov (United States)

    Li, Chunmei; Zhang, Ping; Cheng, Xiuju; Chen, Jianghua

    2013-02-01

    Increasing evidence indicates that the expression of tumor necrosis factor-α (TNF-α) in myocardium correlates with the severity of cardiac dysfunction in septic shock. The aim of this study was to investigate the impact of high-volume hemofiltration (HVHF) on the expression of TNF-α in myocardium in septic shock pigs. Sixteen male Landrace pigs weighing 31 ± 5 kg were randomly assigned to control group (n = 4), septic shock group (n = 6), and HVHF group (septic shock + HVHF, n = 6). All animals were anesthetized and mechanically ventilated. After baseline examinations, septic shock group and HVHF group underwent induction of peritonitis. One hour later, the animals in HVHF group received treatment with HVHF and the treatment was continued for 12 h. As the control of HVHF group, the animals in septic shock group received the same support but hemofiltration. Twelve hours after HVHF therapy, all the animals were sacrificed. TNF-α and nitric oxide (NO) levels in both circulation and myocardium were measured. Compared with those of septic shock animals, the levels of cardiac output, stroke volume, and mean arterial pressure were better maintained in HVHF group. The expression of TNF-α in myocardium in HVHF group was lower than that in septic shock group (44.17 ± 18.70 vs. 92.50 ± 33.89 pg/mg protein, P = 0.015). The difference of TNF-α in circulation between HVHF group and septic shock group was no significance at different time. However, circulating NO in HVHF group was lower than that in septic shock group. These results suggest that HVHF improves hemodynamics and heart dysfunction in septic shock pigs, which may be attributed to reduction of TNF-α in myocardium but not in circulation.

  17. Paradoxical reactions induced by tumor necrosis factor-alpha antagonists: A literature review based on 46 cases

    Directory of Open Access Journals (Sweden)

    Rodica Olteanu

    2016-01-01

    Full Text Available Anti-tumor necrosis factor (TNFα agents have acquired a prominent place in the treatment options for inflammatory disorders. Among the side effects of these agents are the so-called paradoxical reactions which have increasingly been reported in recent years. A review of literature was carried out using Medline (PubMed database from January 2010 to December 2014 to collect all published articles on cases of anti-TNFα-induced psoriasis and psoriatic arthritis. Published articles were identified, reviewed and the relevant data extracted. A total of 22 studies (46 patients fulfilled the inclusion criteria and were selected for analysis. Of the 46 patients, 45 (97.8% developed psoriasis and 1 (2.1% psoriatic arthritis. The mean age of patients was 47 years; three (6.5% patients had a past history of psoriasis. Infliximab caused cutaneous reactions in the most number, 26 (56.5% cases. Thirty seven (80.4%. patients developed primary plaque-type psoriasis. Women accounted for 86.9% of patients. There was complete resolution of psoriasis in 12 (26% patients despite differences in the therapeutic approach. Cessation of the incriminated drug led to resolution of cutaneous lesions in 5 (10.8%, switching to another TNFα antagonist led to resolution in 6 (13% and one (2.1% patient improved despite continuation of the drug. As for the lone case of psoriatic arthritis, drug withdrawal did not result in improvement; only switching to another anti-TNFα agent helped. Since our sample was small, it was not adequately powered to draw any firm conclusions. However, in this analysis, we found that paradoxical reactions occurred predominantly in adult women, there were only isolated cases with a personal history of psoriasis, infliximab was responsible for most cases of these reactions and the most prevalent form was plaque-type psoriasis. The decision whether to continue or discontinue the triggering anti-TNFα agent should be individualized as results are highly

  18. Three-Dimensional Conformal Radiotherapy in Prostate Cancer Patients: Rise in Interleukin 6 (IL-6) but not IL-2, IL-4, IL-5, Tumor Necrosis Factor-{alpha}, MIP-1-{alpha}, and LIF Levels

    Energy Technology Data Exchange (ETDEWEB)

    Oliveira Lopes, Carlos [Universidade do Vale do Paraiba, Centro de Oncologia Radioterapica do Vale do Paraiba, Universidade do Vale do Paraiba Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Sao Jose dos Campos, Sao Paulo (Brazil); Callera, Fernando, E-mail: fcallera@gmail.com [Centro de Hematologia Onco-hematologia e Transplantes de Medula Ossea do Vale do Paraiba, Sao Paulo (Brazil)

    2012-03-15

    Purpose: To investigate the effect of radiotherapy (RT) on serum levels of interleukin-2 (IL-2), IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-{alpha}), macrophage inflammatory protein-1-alpha (MIP-1-{alpha}) and leukemia inhibitory factor (LIF) in patients with prostate cancer. Methods and Materials: Forty eight patients with prostate cancer received three-dimensional conformal blocking radiation therapy with a linear accelerator. IL-2, IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were measured by the related immunoassay kit 1 day before the beginning of RT and during RT at days 15 and 30. Results: The mean IL-2 values were elevated before and during the RT in contrast with those of IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF, which were within the normal range under the same conditions. Regarding markers IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF, comparisons among the three groups (before treatment and 15 and 30 days during RT) did not show significant differences. Although values were within the normal range, there was a significant rise in IL-6 levels at day 15 of RT (p = 0.0049) and a decline at day 30 to levels that were similar to those observed before RT. Conclusions: IL-6 appeared to peak after 15 days of RT before returning to pre-RT levels. In contrast, IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were not sensitive to irradiation. The increased levels of IL-6 following RT without the concurrent elevation of other cytokines involved in the acute phase reaction did not suggest a classical inflammatory response to radiation exposure. Further studies should be designed to elucidate the role of IL-6 levels in patients with prostate cancer treated with RT.

  19. The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.

    LENUS (Irish Health Repository)

    Harmon, D

    2012-02-03

    Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol\\/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg\\/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.

  20. Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist.

    Science.gov (United States)

    Stone, Trevor W; Behan, Wilhelmina M H

    2007-04-01

    Quinolinic acid is an agonist at glutamate receptors sensitive to N-methyl-D-aspartate (NMDA). It has been implicated in neural dysfunction associated with infections, trauma, and ischemia, although its neurotoxic potency is relatively low. This study was designed to examine the effects of a combination of quinolinic acid and the proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Compounds were administered to the hippocampus of anesthetized male rats, animals being allowed to recover for 7 days before histological analysis of the hippocampus for neuronal damage estimated by counting of intact, healthy neurons. A low dose of quinolinic acid or IL-1beta produced no damage by itself, but the two together induced a significant loss of pyramidal neurons in the hippocampus. Higher doses produced almost total loss of pyramidal cells. Intrahippocampal TNF-alpha produced no effect alone but significantly reduced the neuronal loss produced by quinolinic acid. The adenosine A(2A) receptor antagonist ZM241385 reduced neuronal loss produced by the combinations of quinolinic acid and IL-1beta. The results suggest that simultaneous quinolinic acid and IL-1beta, both being induced by cerebral infection or injury, are synergistic in the production of neuronal damage and could together contribute substantially to traumatic, infective, or ischemic cerebral damage. Antagonism of adenosine A(2A) receptors protects neurons against the combination of quinolinic acid and IL-1beta.

  1. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis.

    Science.gov (United States)

    Szretter, Kristy J; Samuel, Melanie A; Gilfillan, Susan; Fuchs, Anja; Colonna, Marco; Diamond, Michael S

    2009-09-01

    Sterile alpha and HEAT/Armadillo motif (SARM) is a highly conserved Toll/interleukin-1 receptor (TIR)-containing adaptor protein that is believed to negatively regulate signaling of the pathogen recognition receptors Toll-like receptor 3 (TLR3) and TLR4. To test its physiological function in the context of a microbial infection, we generated SARM(-/-) mice and evaluated the impact of this deficiency on the pathogenesis of West Nile virus (WNV), a neurotropic flavivirus that requires TLR signaling to restrict infection. Although SARM was preferentially expressed in cells of the central nervous system (CNS), studies with primary macrophages, neurons, or astrocytes showed no difference in viral growth kinetics. In contrast, viral replication was increased specifically in the brainstem of SARM(-/-) mice, and this was associated with enhanced mortality after inoculation with a virulent WNV strain. A deficiency of SARM was also linked to reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. Thus, SARM appears to be unique among the TIR adaptor molecules, since it functions to restrict viral infection and neuronal injury in a brain region-specific manner, possibly by modulating the activation of resident CNS inflammatory cells.

  2. Hypothalamic actions of tumor necrosis factor alpha provide the thermogenic core for the wastage syndrome in cachexia.

    Science.gov (United States)

    Arruda, Ana Paula; Milanski, Marciane; Romanatto, Talita; Solon, Carina; Coope, Andressa; Alberici, Luciane C; Festuccia, William T; Hirabara, Sandro M; Ropelle, Eduardo; Curi, Rui; Carvalheira, José B; Vercesi, Aníbal E; Velloso, Licio A

    2010-02-01

    TNFalpha is an important mediator of catabolism in cachexia. Most of its effects have been characterized in peripheral tissues, such as skeletal muscle and fat. However, by acting directly in the hypothalamus, TNFalpha can activate thermogenesis and modulate food intake. Here we show that high concentration TNFalpha in the hypothalamus leads to increased O(2) consumption/CO(2) production, increased body temperature, and reduced caloric intake, resulting in loss of body mass. Most of the thermogenic response is produced by beta 3-adrenergic signaling to the brown adipose tissue (BAT), leading to increased BAT relative mass, reduction in BAT lipid quantity, and increased BAT mitochondria density. The expression of proteins involved in BAT thermogenesis, such as beta 3-adrenergic receptor, peroxisomal proliferator-activated receptor-gamma coactivator-1 alpha, and uncoupling protein-1, are increased. In the hypothalamus, TNFalpha produces reductions in neuropeptide Y, agouti gene-related peptide, proopiomelanocortin, and melanin-concentrating hormone, and increases CRH and TRH. The activity of the AMP-activated protein kinase signaling pathway is also decreased in the hypothalamus of TNFalpha-treated rats. Upon intracerebroventricular infliximab treatment, tumor-bearing and septic rats present a significantly increased survival. In addition, the systemic inhibition of beta 3-adrenergic signaling results in a reduced body mass loss and increased survival in septic rats. These data suggest hypothalamic TNFalpha action to be important mediator of the wastage syndrome in cachexia.

  3. Tumor necrosis factor expressed by primary hippocampal neurons and SH-SY5Y cells is regulated by alpha(2)-adrenergic receptor activation.

    Science.gov (United States)

    Renauld, A E; Spengler, R N

    2002-01-15

    Neuron expression of the cytokine tumor necrosis factor-alpha (TNF), and the regulation of the levels of TNF by alpha(2)-adrenergic receptor activation were investigated. Adult rat hippocampal neurons and phorbol ester (PMA)-differentiated SH-SY5Y cells were examined. Intracellular levels of TNF mRNA accumulation, as well as TNF protein and that released into the supernatant were quantified by in situ hybridization, immunocytochemistry and bioanalysis, respectively. Both neuron cultures demonstrated constitutive production of TNF. Activation of the alpha(2)-adrenergic receptor increased intracellular levels of TNF mRNA and protein in SH-SY5Y cells after addition of graded concentrations of the selective agonist, Brimonidine (UK-14304) to parallel cultures. Intracellular levels of mRNA were increased in a concentration-dependent fashion within 15 min of UK-14304 addition and were sustained during 24 hr of receptor activation. In addition, the levels of TNF in the supernatant were increased in both types of neuron cultures within 15 min of alpha(2)-adrenergic receptor activation. Furthermore, levels of TNF significantly increased in the supernatants of both neuron cultures after potassium-induced depolarization. A reduction in this depolarization-induced release occurred in hippocampal neuron cultures after exposure to the sympathomimetic tyramine with media replacement to deplete endogenous catecholamines. This finding reveals a role for endogenous catecholamines in the regulation of TNF production. Potassium-induced depolarization resulted in the release of TNF in hippocampal neuron cultures within 15 min but not until 24 hr in SH-SY5Y cultures demonstrating a temporally mediated event dependent upon cell type. Neuron expression of TNF, regulated by alpha(2)-adrenergic receptor activation demonstrates not only how a neuron controls its own production of this pleiotropic cytokine, but also displays a normal role for neurons in directing the many functions of TNF.

  4. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages.

    Science.gov (United States)

    Shioi, Atsushi; Katagi, Miwako; Okuno, Yasuhisa; Mori, Katsuhito; Jono, Shuichi; Koyama, Hidenori; Nishizawa, Yoshiki

    2002-07-12

    Inflammatory cells such as macrophages and T lymphocytes play an important role in vascular calcification associated with atherosclerosis and cardiac valvular disease. In particular, macrophages activated with cytokines derived from T lymphocytes such as interferon-gamma (IFN-gamma) may contribute to the development of vascular calcification. Moreover, we have shown the stimulatory effect of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on in vitro calcification through increasing the expression of alkaline phosphatase (ALP), an ectoenzyme indispensable for bone mineralization, in vascular smooth muscle cells. Therefore, we hypothesized that macrophages may induce calcifying phenotype, especially the expression of ALP in human vascular smooth muscle cells (HVSMCs) in the presence of IFN-gamma and 1,25(OH)2D3. To test this hypothesis, we used cocultures of HVSMCs with human monocytic cell line (THP-1) or peripheral blood monocytes (PBMCs) in the presence of IFN-gamma and 1,25(OH)2D3. THP-1 cells or PBMCs induced ALP activity and its gene expression in HVSMCs and the cells with high expression of ALP calcified their extracellular matrix by the addition of beta-glycerophosphate. Thermostability and immunoassay showed that ALP induced in HVSMCs was bone-specific enzyme. We further identified tumor necrosis factor-alpha (TNF-alpha) and oncostatin M (OSM) as major factors inducing ALP in HVSMCs in the culture supernatants of THP-1 cells. TNF-alpha and OSM, only when applied together, increased ALP activities and in vitro calcification in HVSMCs in the presence of IFN-gamma and 1,25(OH)2D3. These results suggest that macrophages may contribute to the development of vascular calcification through producing various inflammatory mediators, especially TNF-alpha and OSM.

  5. Tumor necrosis factor-alpha (TNF-α enhances functional thermal and chemical responses of TRP cation channels in human synoviocytes

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    Ma Fei

    2009-08-01

    Full Text Available Abstract Background We have shown functional expression of several TRP channels on human synovial cells, proposing significance in known calcium dependent proliferative and secretory responses in joint inflammation. The present study further characterizes synoviocyte TRP expression and activation responses to thermal and osmotic stimuli after pre-treatment with proinflammatory mediator tumor necrosis factor alpha (TNF-α, EC50 1.3221 × 10-10g/L. Results Fluorescent imaging of Fura-2 loaded human SW982 synoviocytes reveals immediate and delayed cytosolic calcium oscillations elicited by (1 TRPV1 agonists capsaicin and resiniferatoxin (20 – 40% of cells, (2 moderate and noxious temperature change, and (3 osmotic stress TRPV4 activation (11.5% of cells. TNF-alpha pre-treatment (1 ng/ml, 8 – 16 hr significantly increases (doubles capsaicin responsive cell numbers and [Ca2+]i spike frequency, as well as enhances average amplitude of temperature induced [Ca2+]i responses. With TNF-alpha pre-treatment for 8, 12, and 16 hr, activation with 36 or 45 degree bath solution induces bimodal [Ca2+]i increase (temperature controlled chamber. Initial temperature induced rapid transient spikes and subsequent slower rise reflect TRPV1 and TRPV4 channel activation, respectively. Only after prolonged TNF-alpha exposure (12 and 16 hr is recruitment of synoviocytes observed with sensitized TRPV4 responses to hypoosmolarity (3–4 fold increase. TNF-alpha increases TRPV1 (8 hr peak and TRPV4 (12 hr peak immunostaining, mRNA and protein expression, with a TRPV1 shift to membrane fractions. Conclusion TNF-α provides differentially enhanced synoviocyte TRPV1 and TRPV4 expression and [Ca2+]i response dependent on the TRP stimulus and time after exposure. Augmented relevance of TRPV1 and TRPV4 as inflammatory conditions persist would provide calcium mediated cell signaling required for pathophysiological responses of synoviocytes in inflammatory pain states.

  6. Correlation Between Adiponectin, Tumor Necrosis Factor-alpha, Insulin Resistance and Atherogenic Dyslipidemia in Non Diabetic Central Obese Males

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    Candra Ninghayu

    2010-04-01

    Full Text Available BACKGROUND: Obesity raises the risk for atherosclerotic cardiovascular disease (ASCVD through many risk factors including atherogenic dyslipidemia. Atherogenic dyslipidemia is characterized by high levels of triglyceride, increased small dense low density lipoprotein particles, and reduced levels of high density lipoprotein cholesterol. The exact mechanisms of central obesity and this atherogenic lipoprotein phenotype (ALP is not clearly understood. Central obesity is characterized by a state of systemic low grade inflammation and insulin resistance. Adipose tissue has recently been shown to secrete a variety of bioactive peptides, called adipocytokines, that can potentially affect glucose and lipid metabolism. The aim of this study was to observe the role of adiponectin, tumor necrosis factor-α (TNF-α and insulin resistance in atherogenic dyslipidemia in nondiabetic central obese males. METHODS: This was a cross-sectional study on 75 non-diabetic central obese male subjects (waist circumferences >90 cm. Adiponectin and TNF-α testing were performed by ELISA; insulin resistance was assessed by the Homeostasis Model Assessment (HOMA index, triglyceride was assessed by GPO-PAP, HDL cholesterol and small dense LDL were measured by homogenous method. Statistical analysis was done by SPSS for Windows v. 11.5 with a significance level at p<0.05. The Pearson and Spearman’s Rho correlation coefficient was used to assess the correlation between various anthropometric and biochemical parameters. RESULTS: There were 75 patients aged 38.0±6.3 years, Adiponectin concentration was 3.55±1.38 μg/ml, HOMA index was 2.28±1.63, TNF-α was 12.42±11.25 pg/ml, triglyceride was 185.17±109.00, HDL-cholesterol was 44.15±9.23 mg/dL, small dense LDL 23.22±12.26 mg/dL. This study revealed that there were correlations between adiponectin and triglyceride (r=-0.236, p=0.042, adiponectin and HDL cholesterol (r=0.300, p=0.009, adiponectin and atherogenic

  7. Monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha is correlated with monocyte infiltration in mouse lipid lesions

    Energy Technology Data Exchange (ETDEWEB)

    Reckless, Jill; Rubin, Edward M.; Verstuyft, Judy B.; Metcalfe, James C.; Grainger, David J.

    1999-01-11

    The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterize early atherogenesis. This focal accumulation of lipids, together with smooth muscle cell proliferation and migration, and the synthesis of extracellular matrix in the intima of large arteries result in the formation of an atherosclerotic plaque. The extent to which the plaque is infiltrated with monocytes appears to be an important determinant of plaque stability. It has been proposed that macrophages secrete an excess of matrix-degrading enzymes over their inhibitors, resulting in conversion of a stable plaque into anunstable plaque that is likely to rupture, resulting in acutemyocardial infarction. Macrophages and T cells constitute {approx}40 percent of the total population of cells in the lipid core region of atherosclerotic plaques. Their recruitment to the lesion may depend on alterations in the adhesive properties of the endothelial surface. Increased endothelial cell permeability and endothelial cell activation are among the earliest changes associated with developing lesions of atherosclerosis. Many of the cell adhesion molecules involved in monocyte recruitment are expressed at low or undetectable levels on normal endothelium but are substantially elevated on the endothelium overlaying atherosclerotic lesions In addition to endothelial cell activation, numerous chemotactic cytokines have also been postulated to be involved in monocyte recruitment. For example, interleukin (IL)-1 and tumor necrosis factor-a (TNF-a) are direct chemoattractants for human monocytes but additionally induce cytoskeletal changes in the endothelium that result in increased permeability. This increased permeability, together with stimulated expression of adhesion molecules such as E-selectin, plays an important part in the local inflammation mediated by TNF-a and IL-1. In addition, a large number of other proinflammatory cytokines, including macrophage

  8. Imaging Tumor Necrosis with Ferumoxytol.

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    Maryam Aghighi

    high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.

  9. In vitro inhibition of enterobacteria-reactive CD4+Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Mangano, K.; Sardesai, N.; D'Alcamo, M.;

    2008-01-01

    VGX-1027 is an isozaxoline compound that has recently been found to primarily target the function of murine macrophages but not of T cells, inhibiting secretion of tumor necrosis factor (TNF)-alpha in response to different Toll-like receptor agonists in vitro and in vivo. The well-defined role...

  10. CLINICAL-EXPERIENCE WITH HIGH-DOSE TUMOR-NECROSIS-FACTOR-ALPHA IN REGIONAL THERAPY OF ADVANCED MELANOMA

    NARCIS (Netherlands)

    LEJEUNE, F; LIENARD, D; EGGERMONT, A; KOOPS, HS; KROON, B; GERAIN, J; ROSENKAIMER, F; SCHMITZ, P

    1994-01-01

    Isolated perfusion of the limbs (ILP) allows the delivery of high dose rTNF alpha in a closed system with acceptable side-effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In melanoma-in-t

  11. Combined effect of tumor necrosis factor-alpha and ionizing radiation on the induction of apoptosis in 5637 bladder carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Baierlein, S.A.; Distel, L.; Sieber, R.; Weiss, C.; Roedel, C.; Sauer, R.; Roedel, F. [Dept. of Radiation Oncology, Friedrich Alexander Univ. Erlangen-Nuremberg (Germany)

    2006-08-15

    Background and Purpose: Apoptosis can be induced by distinct but overlapping pathways. Ionizing radiation induces apoptosis by an ''intrinsic'', mitochondria-dependent pathway. Ligation of tumor necrosis factor-(TNF-){alpha}, FAS (CD95) or TRAIL receptors are typical representatives of an extrinsic, death-receptor-mediated pathway. In this study the effect of irradiation, treatment with the cytokine TNF-{alpha}, or a combination of both on the induction of apoptosis and clonogenic survival of bladder carcinoma cells was investigated. Material and Methods: 5637 bladder carcinoma cells were treated with different concentrations of recombinant TNF-{alpha} (0-10 ng/ml), irradiated with single doses ranging from 0.5 to 10 Gy, or a combination of both modalities. Apoptotic cells were quantified by the TUNEL assay up to 96 h following treatment, clonogenic cell survival by a clonogenic assay. Synergistic effects of both modalities were evaluated using isobolographic analysis. Results: Irradiation of 5637 carcinoma cells resulted in a discontinuous dose dependence of the apoptotic fraction with a pronounced increase in the range of 0-2 Gy and a slighter increase at 2-10 Gy. The percentage of apoptotic carcinoma cells also increased continuously after treatment with lower concentrations of TNF-{alpha} reaching a plateau at concentrations of 5.0-10.0 ng/ml. Isobolographic analysis revealed a supraadditive interrelationship between irradiation and TNF-{alpha} in the range between 0.005 and 0.5 ng/ml, and an additive effect for TNF-{alpha} concentrations > 0.5 ng/ml. The additive effects were confirmed in clonogenic survival assays with reduced survival fractions following combined TNF-{alpha} administration and irradiation. Conclusion: The combination of two apoptosis-inducing modalities resulted in a synergistic effect on the induction of apoptosis in 5637 bladder carcinoma cells. Although a radiosensitizing effect still has to be proven in animal models

  12. Moxibustion inhibits interleukin-12 and tumor necrosis factor alpha and modulates intestinal flora in rat with ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    Xiao-Mei Wang; Yuan Lu; Lu-Yi Wu; Shu-Guang Yu; Bai-Xiao Zhao; Hong-Yi Hu; Huan-Gan Wu

    2012-01-01

    AIM:To investigate the effect of moxibustion on intestinal flora and release of interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) from the colon in rat with ulcerative colitis (UC).METHODS:A rat model of UC was established by local stimulation of the intestine with supernatant from colonic contents harvested from human UC patients.A total of 40 male Sprague-Dawley rats were randomly divided into the following groups:normal (sham),model (UC),herb-partition moxibustion (HPM-treated),and positive control sulfasalazine (SA-treated).Rats treated with HPM received HPM at acupuncture points ST25 and RN6,once a day for 15 min,for a total of 8 d.Rats in the SA group were perfused with SA twice a day for 8 d.The colonic histopathology was observed by hematoxylin-eosin.The levels of intestinal flora,including Bifidobacterium,Lactobacillus,Escherichia coli (E.coli),and Bacteroides fragilis (B.fragilis),were tested by real-time quantitative polymerase chain reaction to detect bacterial 16S rRNA/DNA in order to determine DNA copy numbers of each specific species.Immunohistochemical assays were used to observe the expression of TNF-α and IL-12 in the rat colons.RESULTS:HPM treatment inhibited immunopathology in colonic tissues of UC rats; the general morphological score and the immunopathological score were significantly decreased in the HPM and SA groups compared with the model group [3.5 (2.0-4.0),3.0 (1.5-3.5) vs 6.0 (5.5-7.0),P < 0.05 for the general morphological score,and 3.00 (2.00-3.50),3.00 (2.50-3.50) vs 5.00 (4.50-5.50),P < 0.01 for the immunopathological score].As measured by DNA copy number,we found that Bilidobacterium and Lactobacillus,which are associated with a healthy colon,were significantly higher in the HPM and SA groups than in the model group (1.395± 1.339,1.461 ± 1.152 vs 0.045 ± 0.036,P < 0.01 for Bifidobacterium,and 0.395 ± 0.325,0.851 ± 0.651 vs 0.0015 ± 0.0014,P < 0.01 for Lactobacillus).On the other hand,E.coli and B

  13. Influence of Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Interleukin 10 Genes on the Risk of Liver Cirrhosis in HIV-HCV Coinfected Patients.

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    Sara Corchado

    Full Text Available Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP at position -238 and -308 of the tumor necrosis factor alpha (TNF-α and -592 of the interleukin-10 (IL-10 promotor genes and of classical factors (age, alcohol, immunodepression, antirretroviral therapy on the risk of liver cirrhosis in human immunodeficiency (HIV-hepatitis C (HCV virus coinfected patients.Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load and HCV-related (serum ALT concentration, HCV viral load, HCV genotype characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α and -592 of the interleukin-10 (IL-10 promotor genes were studied.Evolution time of the infection was 21 years in both patients' groups (chronic hepatitis and liver cirrhosis. The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection, a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis.It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position, above other factors previously accepted (age, gender, alcohol, immunodepression, on the evolution to liver cirrhosis among HIV-infected patients with established chronic

  14. Recombinant human tumor necrosis factor alpha does not potentiate cell killing after photodynamic therapy with a silicon phthalocyanine in A431 human epidermoid carcinoma cells.

    Science.gov (United States)

    Azizuddin, K; Kalka, K; Chiu, S M; Ahmad, N; Mukhtar, H; Separovic, D

    2001-02-01

    Photodynamic therapy (PDT) is a novel cancer treatment utilizing a photosensitizer, visible light and oxygen. PDT with the silicon phthalocyanine Pc 4, a new photosensitizer, is highly effective in cancer cell destruction and tumor ablation. The mechanisms underlying cancer cell killing by PDT are not fully understood. Tumor necrosis factor alpha (TNF) is a multifunctional cytokine that has been implicated in photocytotoxicity. We asked whether recombinant human TNF (rhTNF) affects Pc 4-PDT cytotoxicity in A431 human epidermoid carcinoma cells. Co-treatment of A431 cells with various doses of Pc 4-PDT and a sub-lethal rhTNF dose led to a sub-additive reduction in cell survival. In addition, in the presence of Pc 4-PDT or rhTNF, caspase-3 activity and apoptosis were induced. The combined treatment, however, did not potentiate either caspase-3 activity or apoptosis. Similar to previous findings we observed that Pc 4-PDT initiated a time-dependent extracellular TNF accumulation. The data suggest that: a) PDT and rhTNF induce cancer cell killing through different mechanisms; and b) Pc 4-PDT-induced TNF production is a stress response that may not directly affect photocytotoxicity.

  15. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic

    DEFF Research Database (Denmark)

    Theibich, Ali; Dreyer, Lene; Magyari, Melinda;

    2014-01-01

    Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling...... multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after...... treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all...

  16. Lipopolysaccharide (LPS) processing by Kupffer cells releases a modified LPS with increased hepatocyte binding and decreased tumor necrosis factor-alpha stimulatory capacity.

    Science.gov (United States)

    Treon, S P; Thomas, P; Broitman, S A

    1993-02-01

    Normal physiological clearance of gut-derived endotoxin lipopolysaccharide [LPS] has been described previously; initially, there is uptake by Kupffer cells (KC), then release of modified LPS, followed by hepatocyte uptake. Previous work in our laboratories indicated that LPS is structurally modified with loss of carbohydrate prior to its release by KC. In this study, we functionally characterize KC modified LPS. KC-modified 125I-LPS was prepared from primary rat KC. Escherichia coli 0127:B8 native 125I-LPS or KC-modified 125I-LPS (40 ng) was incubated for 1 hr with 1 x 10E6 primary hepatocytes. The binding of KC-modified LPS was 4.33-fold higher than native LPS (P = 0.0024). Binding analysis studies were conducted to determine the region of KC-modified LPS responsible for enhanced hepatocyte binding. KC-modified Salmonella minnesota LPS was competed with 100-fold excess native or mutant (Ra, Rc, Rd, or Re) strains of LPS or Lipid A with no decrease to hepatocyte binding. S. minnesota-native 125I-LPS was compared with KC-modified 125I-LPS in a study to assess induction of tumor necrosis factor (TNF)-gamma by rat peritoneal macrophages. Native or KC-modified 125I-LPS (100 ng) was presented to 1 x 10E7 peritoneal macrophages for 6 hr. TNF-alpha was measured in supernatants using the WEHI-164 cytotoxicity assay. Native LPS induced 5.7-fold higher TNF-alpha levels than KC-modified LPS (P < 0.0001). The above data suggest that structural alterations in KC-modified LPS are accompanied by functional alterations resulting in enhanced hepatocyte binding and decreased TNF-alpha release. The latter result implies that an early step in LPS detoxification occurs in the KC in which LPS is modified to prevent elicitation of biologically active cytokines.

  17. Inhibition of tumor necrosis factor-alpha by sodium ferulate in protecting neurons from beta-amyloid induced damage

    Institute of Scientific and Technical Information of China (English)

    Suyan Yao; Deyu Zheng; Zhuo Liu; Ying Jin

    2006-01-01

    BACKGROUND: Sodium ferulate (SF) has an effect of anti-inflammation; however, whether it can inhibit beta-amyloid (Aβ) induced damage or not should be further studied.OBJECTIVE: To investigate the effects of SF on neurotoxicity mediated by Aβ-induced macrophage activation via inhibiting tumor necrosis factor-α (TNF-α) in vitro.DESTGN: A contrast experiment based on cells.SETTrNG: Departments of Pathophysiology, Pharmacology and Anatomy, Liaoning Medical College.MATERTALS: A total of 36 Kunming mice aged 8-10 weeks and some SD rats aged 2-3 days of both genders were selected in this study. Main reagents were detailed as follows: Aβ peptide (Sigma Company); SF (purity >99%, Suzhou Changtong Chemical Co., Ltd.); lactate dehydrogenase (LDH) assay kit (Bangding Biological Engineering Co., Beijing, China); microtubule-associated protein 2 (MAP-2) monoclonal antibodies and TNF-αmonoclonal antibodies (Boster Biological Engineering Co., Wuhan, China).METHODS: The experiment was carried out in Laboratories of Pharmacology and Anatomy, Liaoning Medical College from May to December 2004. Cerebellum was obtained from rats under sterile condition to culture neurons and macrophages taken from mice abdominal cavity. Later, two parallel experiments were performed as follows: ① Macrophages culture groups: In normal control group, macrophages were cultured in DMEM after being seeded. In Aβ group, neurotoxic form of Aβ was added into DMEM media with final concentration of 10 μmol/L after macrophages were seeded for 24 hours. In Aβ+SF group, ten minutes after Aβ treatment, for 10, 100, 500 μmol/L and 1 mmol/L of SF were added to the media of the macrophages culture. ②Macrophages-neurons co-cultured groups: Control macrophages-neurons were co-cultured. Aβ group:Neurotoxic form of Aβ was added into the media with concentration of 10 iμmol/L after macrophages were seeded in the neurons cultured wells for 24 hours. Aβ±SF group: Ten minutes after Aβ treatment, 10

  18. Tumor necrosis factor-alpha G-238A polymorphism and coronary artery disease risk: a meta-analysis of 4,222 patients and 4,832 controls

    Directory of Open Access Journals (Sweden)

    Hua XP

    2015-09-01

    Full Text Available Xian-Ping Hua,1,* Xiao-Dong Zhang,2,* Joey SW Kwong,3,* Xian-Tao Zeng,4 Zhen-Jian Zhang,1 Wan-Lin Wei21Department of Cardiology, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei Province, 2Department of Cardiology and 4th Cadres Ward, General Hospital of Beijing Military Command, Beijing, 3Chinese Evidence-Based Medicine Center and Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, 4Center for Evidence-Based and Translational Medicine, Zhongnan Hospital, Wuhan University, Wuhan, People’s Republic of China*These authors contributed equally to this workBackground: The aim of the present study was to investigate the association between tumor necrosis factor-alpha (TNF-α gene G-238A polymorphism and risk of coronary artery disease (CAD using a meta-analytical approach.Methods: The PubMed and Embase databases were searched for relevant publications up to January 13, 2015. Four authors (XPH, XDZ, XTZ, and ZJZ independently selected the studies, extracted, and analyzed the data using the Comprehensive Meta-Analysis software. The sensitivity and subgroups analyses were also performed. Either a fixed effects or a random effects model was used to estimate pooled odds ratios (ORs and their 95% confidence intervals (CIs.Results: Finally, ten articles including eleven case-control studies involving 4,222 patients and 4,832 controls were yielded. The results indicated no significant association between G-238A polymorphism and CAD risk (A vs G: OR =1.08, 95% CI =0.89–1.30; AA vs GG: OR =1.15, 95% CI =0.59–2.25; GA vs GG: OR =1.14, 95% CI =0.88–1.48; AA vs [GG + GA]: OR =1.09, 95% CI =0.56–2.14; (GA + AA vs GG: OR =1.11, 95% CI =0.90–1.38. In the subgroup analyses, similar results were obtained with overall populations. The sensitivity analyses showed that the overall results were robust. No publication bias was detected.Conclusion: Based on current evidence, we can conclude that TNF-α G-238A polymorphism

  19. Polymorphisms in the tumor necrosis factor-alpha gene in Turkish women with pre-eclampsia and eclampsia

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    Demirkazik,Ayse

    2007-06-01

    Full Text Available The genetic background predisposing pregnant women to pre-eclampsia/eclampsia (PE/E is still unknown. The aim of the current study was to investigate whether there is an association between the TNF-alpha-308 and 850 polymorphisms and PE or eclampsia. In this study, 40 cases of eclampsia, 113 cases of PE and 80 normotensive control cases were genotyped for the TNF-alpha-G-308A and C-850 polymorphisms. At position 308, the replacement of Guanine with Adenosine was denoted as TNF2. We found a significant difference between the TNF2 allele frequencies of the eclamptic, pre-eclamptic and normotensive controls. TNF2 (AA polymorphism frequency was significantly higher among the eclamptics and pre-eclamptics (control : 5%, PE : 13.3%, E : 12.9%. A significantly different genotype distribution of C-850T polymorphism was observed between the PE/E and control groups, with the frequency of the variant TT genotype being significantly reduced in the preeclamptics (PE : 17% ; E : 17.5% when compared with the control group (24.3%. We have demonstrated an association between TNF-alpha polymorphisms and pre-eclampsia susceptibility. However, it is not known whether C-850T polymorphism has a functional effect on the TNF-alpha gene. In addition, it was not possible to determine whether this polymorphism promotes the progression from PE to eclampsia because of no statistically significant difference between eclampsia and the controls.

  20. Inflammatory cascades driven by tumor necrosis factor-alpha play a major role in the progression of acute liver failure and its neurological complications.

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    Anne Chastre

    Full Text Available BACKGROUND/AIMS: Acute liver failure (ALF due to ischemic or toxic liver injury is a clinical condition that results from massive loss of hepatocytes and may lead to hepatic encephalopathy (HE, a serious neuropsychiatric complication. Although increased expression of tumor necrosis factor-alpha (TNF-α in liver, plasma and brain has been observed, conflicting results exist concerning its roles in drug-induced liver injury and on the progression of HE. The present study aimed to investigate the therapeutic value of etanercept, a TNF-α neutralizing molecule, on the progression of liver injury and HE in mice with ALF resulting from azoxymethane (AOM hepatotoxicity. METHODS/PRINCIPAL FINDINGS: Mice were administered saline or etanercept (10 mg/kg; i.p. 30 minutes prior to, or up to 6 h after AOM. Etanercept-treated ALF mice were sacrificed in parallel with vehicle-treated comatose ALF mice and controls. AOM induced severe hepatic necrosis, leading to HE, and etanercept administered prior or up to 3 h after AOM significantly delayed the onset of coma stages of HE. Etanercept pretreatment attenuated AOM-induced liver injury, as assessed by histological examination, plasma ammonia and transaminase levels, and by hepatic glutathione content. Peripheral inflammation was significantly reduced by etanercept as shown by decreased plasma IL-6 (4.1-fold; p<0.001 and CD40L levels (3.7-fold; p<0.001 compared to saline-treated ALF mice. Etanercept also decreased IL-6 levels in brain (1.2-fold; p<0.05, attenuated microglial activation (assessed by OX-42 immunoreactivity, and increased brain glutathione concentrations. CONCLUSIONS: These results indicate that systemic sequestration of TNF-α attenuates both peripheral and cerebral inflammation leading to delayed progression of liver disease and HE in mice with ALF due to toxic liver injury. These results suggest that etanercept may provide a novel therapeutic approach for the management of ALF patients awaiting

  1. Expression of anti-tumor necrosis factor alpha (TNFα) single-chain variable fragment (scFv) in Spirodela punctata plants transformed with Agrobacterium tumefaciens.

    Science.gov (United States)

    Balaji, Parthasarathy; Satheeshkumar, P K; Venkataraman, Krishnan; Vijayalakshmi, M A

    2016-05-01

    Therapeutic antibodies against tumor necrosis factor alpha (TNFα) have been considered effective for some of the autoimmune diseases such as rheumatoid arthritis, Crohn's diseases, and so on. But associated limitations of the current therapeutics in terms of cost, availability, and immunogenicity have necessitated the need for alternative candidates. Single-chain variable fragment (scFv) can negate the limitations tagged with the anti-TNFα therapeutics to a greater extent. In the present study, Spirodela punctata plants were transformed with anti-TNFα through in planta transformation using Agrobacterium tumefaciens strain, EHA105. Instead of cefotaxime, garlic extract (1 mg/mL) was used to remove the agrobacterial cells after cocultivation. To the best of our knowledge, this report shows for the first time the application of plant extracts in transgenic plant development. 95% of the plants survived screening under hygromycin. ScFv cDNA integration in the plant genomic DNA was confirmed at the molecular level by PCR. The transgenic protein expression was followed up to 10 months. Expression of scFv was confirmed by immunodot blot. Protein expression levels of up to 6.3% of total soluble protein were observed. β-Glucuronidase and green fluorescent protein expressions were also detected in the antibiotic resistant plants. The paper shows the generation of transgenic Spirodela punctuata plants through in planta transformation.

  2. Polymorphisms of Tumor Necrosis Factor Alpha in Moroccan Patients with Gastric Pathology: New Single-Nucleotide Polymorphisms in TNF-α−193 (G/A

    Directory of Open Access Journals (Sweden)

    A. Essadik

    2015-01-01

    Full Text Available Polymorphisms in tumor necrosis factor alpha (TNF-α gene are emerging as key determinants of gastric diseases. The TNF-α−308 (G/A and TNF-α−238 (G/A single-nucleotide polymorphisms SNPs are the most extensively studied. However, all these studies are conducted in Caucasian and Asian populations. Thus, for the first time in Africa, we sought to investigate whether polymorphisms in TNF-α gene were associated with the development of gastric pathology in Morocco. Two SNPs located in the promoter region (positions −308 and −238 in TNF-α gene were genotyped in 244 individuals (170 patients and 74 healthy controls. Odds ratios (ORs and 95% confidence intervals (CI were estimated using logistic regression analysis. The TNF-α−238 (G/A genotype was significantly associated with a high risk of gastritis and gastric cancer (GC (P=0.001 and P=0.002, resp.. Furthermore, a new polymorphism located in the promoter region at position −193 in TNF-α gene was identified. The distribution of this SNP was markedly different in patients suffering from ulcers. The association between TNF-α−193 (G/A genotype and high risk of ulcer was significant (P=0.03. These results suggest that the TNF-α−193 (G/A allele has a protective function against gastric cancer by developing ulcer.

  3. Increased tumor necrosis factor alpha and interleukin-6 serum levels and their correlation with laboratory parameters in patients with imported malaria

    Directory of Open Access Journals (Sweden)

    Poluga Jasmina

    2012-01-01

    Full Text Available In malaria, blood concentrations of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α and interleukin (IL-6, are increased. In a study which included 34 patients, TNF-α and IL-6 were examined in two phases, immediately after the admission of patients, and at the end of antimalarial therapy, when the parasitemia was negative. The results show a significant increase of TNF-α and IL-6 in the first phase, before the effects of antimalarial therapy. A very strong correlation between TNF-α and IL-6 is also confirmed, which suggests their coordinated production. Increased TNF-α values were correlated with an older age, the level of parasitemia, the number of platelets and leukocytes, elevated values of procalcitonin, D-dimer and lactate dehydrogenasе, and lower values of serum iron and antithrombin. Increased values of IL-6 were correlated with the level of parasitemia, the number of platelets and leukocytes, and elevated values of D-dimer and lactates.

  4. Tumor Necrosis Factor-Alpha Gene Promoter −308G/A and −238G/A Polymorphisms in Mexican Patients with Type 2 Diabetes Mellitus

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    Juan Manuel Guzmán-Flores

    2011-01-01

    Full Text Available The association between some Tumor necrosis factor-alpha (TNF-α promoter polymorphisms and Type 2 diabetes mellitus (T2DM remains controversial. Ethnic differences may play a role in these conflicting results. The aim of this study was to investigate the association between −308G/A and −238G/A polymorphisms located in the promoter region of the TNF-α gene and T2DM in Mexican mestizo patients. Nine hundred four individuals (259 patients with T2DM and 645 controls were genotyped for the −308G/A and −238G/A polymorphisms by PCR—RFLP. We found that the −238A allele increased the risk of developing T2DM in Mexican patients (OR = 1.57, 95% CI: 1.07–2.29; p = 0.018. Moreover, we found that the frequency of the GA haplotype (created by the −308G and −238A alleles was significantly increased in patients with T2DM when compared with controls (OR = 1.56, 95% CI: 1.05–2.31; p = 0.026. Our results suggest that the −238G/A polymorphism and a specific haplotype (GA are genetic risk factors for the development of T2DM in Mexican population.

  5. Metabolism studies of a small-molecule tumor necrosis factor-alpha (TNF-α) inhibitor, UTL-5b (GBL-5b).

    Science.gov (United States)

    Shaw, Jiajiu; Shay, Brian; Jiang, Jack; Valeriote, Frederick; Chen, Ben

    2012-06-01

    UTL-5b is an anti-inflammatory and anti-arthritic small-molecule tumor necrosis factor-alpha inhibitor and a structural analogue of the anti-arthritic drug, leflunomide. Leflunomide is known to be metabolized to teriflunomide, but the metabolites of UTL-5b have not been reported. The objective of this study was to investigate whether UTL-5b has a similar metabolic behavior as leflunomide. Preliminary studies showed that when exposed to microsomes in vitro with or without NADPH, UTL-5b disappeared within 30 min. To further investigate the microsomal metabolism, liquid chromatography-ultraviolet (LC-UV) and LC/tandem mass spectrometry (LC-MS/MS) were employed to, respectively, monitor the microsomal metabolites and identify the structure of the metabolites using LC-full scan MS and LC combined with multiple-ion monitoring MS. Fragmentation determination was analyzed by two types of scans: product ion scans and precursor ion scan. The in vitro microsomal treatment of UTL-5b resulted in two major metabolites: 5-methylisoxazole-3-carboxylic acid and 2-chloroaniline. Thus, the in vitro metabolic behavior of UTL-5b appears to be different from that of leflunomide in that the isoxazole ring is cleaved.

  6. Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis.

    Science.gov (United States)

    Garraway, Sandra M; Woller, Sarah A; Huie, J Russell; Hartman, John J; Hook, Michelle A; Miranda, Rajesh C; Huang, Yung-Jen; Ferguson, Adam R; Grau, James W

    2014-11-01

    We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered 1 day after SCI on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days after treatment. In addition, because the proinflammatory cytokine tumor necrosis factor alpha (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation after SCI induced mechanical sensitivity by 24h. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3, indicative of active apoptosis at a time point consistent with the onset of mechanical allodynia. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24h after stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.

  7. Analysis of Subcellular RNA Fractions Revealed a Transcription-Independent Effect of Tumor Necrosis Factor Alpha on Splicing, Mediated by Spt5.

    Science.gov (United States)

    Diamant, Gil; Eisenbaum, Tal; Leshkowitz, Dena; Dikstein, Rivka

    2016-05-01

    The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) modulates the expression of many genes, primarily through activation of NF-κB. Here, we examined the global effects of the elongation factor Spt5 on nascent and mature mRNAs of TNF-α-induced cells using chromatin and cytosolic subcellular fractions. We identified several classes of TNF-α-induced genes controlled at the level of transcription, splicing, and chromatin retention. Spt5 was found to facilitate splicing and chromatin release in genes displaying high induction rates. Further analysis revealed striking effects of TNF-α on the splicing of 25% of expressed genes; the vast majority were not transcriptionally induced. Splicing enhancement of noninduced genes by TNF-α was transient and independent of NF-κB. Investigating the underlying basis, we found that Spt5 is required for the splicing facilitation of the noninduced genes. In line with this, Spt5 interacts with Sm core protein splicing factors. Furthermore, following TNF-α treatment, levels of RNA polymerase II (Pol II) but not Spt5 are reduced from the splicing-induced genes, suggesting that these genes become enriched with a Pol II-Spt5 form. Our findings revealed the Pol II-Spt5 complex as a highly competent coordinator of cotranscriptional splicing.

  8. Construction of shuttle, expression vector of human tumor necrosis factor alpha (hTNF-α) gene and its expression in a cyanobacterium, Anabaena sp. PCC 7120

    Institute of Scientific and Technical Information of China (English)

    刘凤龙; 施定基; 商之狄; 邵宁; 徐旭东; 钟泽璞; 张宏斌; 吴锦银; 王捷; 江悦华; 赵树进; 林晨; 张雪艳; 吴旻; 彭国宏; 张海霞; 曾呈奎

    1999-01-01

    The construction of the shuttle, expression vector of human tumor necrosis factor alpha (hTNF-a) gene and its expression in a cyanobacterium Anabaena sp. PCC 7120 was reported. The 700-bp hTNF cDNA fragments have been recovered from plasmid pRL-rhTNF, then inserted downstream of the promoter PpsbA in the plasmid pRL439. The resultant intermediary plasmid pRL-TC has further been combined with the shuttle vector pDC-8 to get the shuttle, expression vector pDC-TNF. The expression of the rhTNF gene in Escherichia coli has been analyzed by SDS-PAGE and thin-layer scanning, and the results show that the expressed TNF protein with these two vectors is 16.9 percent (pRL-TC) and 15.0 percent (pDC-TNF) of the total proteins in the cells, respectively, while the expression level of TNF gene in plasmid pRL-rhTNF is only 11.8 percent. Combined with the participation of the conjugal and helper plasmids, pDC-TNF has been introduced into Anabaena sp PCC 7120 by triparental conjugative transfer, and the stable transgenic

  9. Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: a prospective longitudinal study.

    Science.gov (United States)

    Li, Zezhi; Qi, Dake; Chen, Jun; Zhang, Chen; Yi, Zhenghui; Yuan, Chengmei; Wang, Zuowei; Hong, Wu; Yu, Shunying; Cui, Donghong; Fang, Yiru

    2013-01-01

    Although tumor necrosis factor-alpha (TNF-α) has been recognized to be involved in the pathogenesis of major depressive disorder (MDD) for a long time, only few studies so far investigated the effects of antidepressant, venlafaxine on TNF-α and the results are inconsistent. Moreover, the association between plasma TNF-α levels and suicide accompanied with MDD is entirely unknown. To elucidate these relationships, in the present study, 64 first-episode drug-naïve MDD patients and 64 matched healthy controls were recruited. Total 61 MDD patients received 8-week venlafaxine treatment and they were divided into responders and non-responders according to the reduction rate of HRSD-17. Prior to venlafaxine treatment, both responders and non-responders shared a similar plasma TNF-α (p=0.33), which was significantly decreased following venlafaxine treatment (pTNF-α (p=0.01), which was associated with the greater reduction rate of HRSD-17 (B=1.02, p=0.01). In addition, the plasma TNF-α levels were equally higher in both suicidal and non-suicidal MDD patients (p=0.84) compared to the healthy controls on admission (p=0.001, p=0.03, respectively). Together, our data suggest that MDD per se rather than suicide is associated with the elevated plasma TNF-α, which can be inhibited with venlfaxine monotherapy. The extent of TNF-α reduction may be associated with the efficiency of venlafaxine.

  10. ASTAXANTHIN MENURUNKAN KADAR VASCULAR ENDOTHELIAL GROWTH FACTOR, TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN-6, DAN NITRIC OXIDE PADA NONPROLIFERATIVE DIABETIC RETINOPATHY RINGAN: UJI KLINIS TERKENDALI

    Directory of Open Access Journals (Sweden)

    Ni Made Laksmi Utari

    2015-01-01

    Full Text Available Diabetic Retinopathy (DR merupakan komplikasi mikrovaskular pada Diabetes Mellitus (DM dan penyebab kebutaan paling sering pada usia produktif. Hiperglikemia menyebabkan terjadinya reaksiinflamasi dan stres oksidatif  dalam patogenesis DR dipaparkan oleh beberapa peneliti, namun peran antioksidan dalam mengurangi progresifitas DR masih menjadi perdebatan. Penelitian ini bertujuanuntuk mengetahui pemberian astaxanthin 8 mg dapat menurunkan kadar Vascular Endothelial Growth Factor (VEGF, Tumor Necrosis Factor-alpha (TNF-á, Interleukin-6 (IL-6 dan Nitric Oxide (NO padapenderita Non Proliferative Diabetic Retinopathy (NPDR ringan. Penelitian clinical trial dengan perluasan Randomized, Double Blinded, Placebo-Control, Pre and Posttest Group Design ini dilaksanakanpada bulan Juli 2013 - Desember 2013 di Poliklinik Mata RSUP Sanglah Denpasar Bali. Jumlah sampel yang memenuhi kriteria eligibilitas sebanyak 40 pasien NPDR ringan terbagi menjadi 20 pasien  sebagai kelompok perlakuan yang diberikan astaxanthin 8 mg dan 20 pasien NPDR ringan yang diberikan plasebo sebagai kelompok kontrol. Pengambilan sampel darah vena untuk pemeriksaan dilakukan sebelum dan setelah pemberian astaxanthin 8 mg serta plasebo selama 4 minggu. Perbedaan kadar rerata VEGF, TNF-á, IL-6 dan NO dianalisis dengan uji-t jika distribusi data normal dan uji Mann-whitney jika distribusi data tidak  normal. Hasil penelitian ini diharapkan dapat memberikaninformasi mengenai hubungan VEGF, TNF-á, IL-6, dan NO dalam perkembangan NPDR ringan serta manfaat pemberian astaxanthin dalam perkembangan NPDR ringan. [MEDICINA 2014;45:31-37

  11. The Effect of a Prophylactic Dose of Ibuprofen on Plasma Level of Interleukin 1, Interleukin 6 and Tumor Necrosis Factor-Alpha in a 1500 m Running Practice

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    Gholamreza Sepehri

    2011-01-01

    Full Text Available Problem statement: there are controversies about the effects of anti-inflammatory drugs on exercised induced changes on plasma cytokines in untrained male athletes, so the primary purpose of this study was to measure the influence of a prophylactic dose of ibuprofen use on plasma cytokines during a 1500 m running race. Approach: Subjects were 10 untrained male Medical University students who consumed 400 mg ibuprofen two hours before the 1500 m running practice and 10 controls that competed in the race but avoided ibuprofen and all other medications. Blood samples were collected before, 1h and 24 h following the 1500 m exercise bout to measure plasma concentrations of interleukin-1 beta (IL-1β , interleukin-6(IL-6 and tumor necrosis factor alpha (TNF- α . Results: There were not any significant differences between plasma concentration of IL-1β, IL-6 and TNF- α during the study period. Also the data showed that there were not any significant differences between plasma level of IL-1β, IL-6 and TNF- α in ibuprofen and control group during the study period. Conclusions/Recommendation: Our result showed that a prophylactic dose of ibuprofen did not affect acute inflammatory cytokines levels (IL-1β, IL-6 and TNF- α in untrained healthy young males. So the etiology of the muscle soreness in athletes actively participating in sport races seems to be independent of inflammatory processes.

  12. Increased pulmonary secretion of tumor necrosis factor-alpha in calves experimentally infected with bovine respiratory syncytial virus

    DEFF Research Database (Denmark)

    Rontved, C. M.; Tjørnehøj, Kirsten; Viuff, B.

    2000-01-01

    Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease among calves in the Danish cattle industry. An experimental BRSV infection model was used to study the pathogenesis of the disease in calves. Broncho alveolar lung lavage (BAL) was performed on 28 Jersey calves...... of TNF-alpha appeared on the days where severe lung lesions and clinical signs were obvious and the amounts of BRSV-antigen were at their greatest. Although Pasteurellaceae were isolated from some of the BRSV-infected calves, calves treated with antibiotics before and through the whole period...

  13. Natural soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17).

    Science.gov (United States)

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Ludwig, Andreas; Rose-John, Stefan; Saftig, Paul; Borden, Ernest C; Bulfone-Paus, Silvia

    2004-09-24

    This study shows that the high affinity alpha-chain of the interleukin (IL)-15 receptor exists not only in membrane-anchored but also in soluble form. Soluble IL-15Ralpha (sIL-15Ralpha) can be detected in mouse sera and cell-conditioned media by enzyme-linked immunosorbent assay and by immunoprecipitation and Western blotting. This protein has a molecular mass of about 30 kDa because of the presence of a single N-glycosylation site, which is reduced to 26 kDa after N-glycosidase treatment. Transmembrane IL-15Ralpha is constitutively converted into its soluble form by proteolytic cleavage that involves tumor necrosis factor-alpha-converting enzyme (TACE), and this process is further enhanced by phorbol 12-myristate 13-acetate (PMA) stimulation. The hydroxamate GW280264X, which is capable of blocking TACE and the closely related disintegrin-like metalloproteinase 10 (ADAM10), effectively inhibited both spontaneous and PMA-inducible cleavage of IL-15Ralpha, whereas GI254023X, which preferentially blocks ADAM10, was ineffective. Overexpression of TACE but not ADAM10 in COS-7 cells enhanced the constitutive and PMA-inducible cleavage of IL-15Ralpha. Moreover, murine fibroblasts deficient in TACE but not ADAM10 expression exhibited a significant reduction in the spontaneous and inducible IL-15Ralpha shedding, whereas a reconstitution of TACE in these cells restored the release of sIL-15Ralpha, thereby suggesting that TACE-mediated proteolysis may represent a major mechanism for sIL-15Ralpha generation in mice. The existence of natural sIL-15Ralpha offers novel insights into the complex biology of IL-15 and envisages a new level for therapeutic intervention.

  14. Haemophilus ducreyi lipooligosaccharides induce expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase via type I interferons and tumor necrosis factor alpha in human dendritic cells.

    Science.gov (United States)

    Li, Wei; Katz, Barry P; Spinola, Stanley M

    2011-08-01

    Haemophilus ducreyi causes chancroid, a genital ulcer disease. In human inoculation experiments, most volunteers fail to clear the bacteria despite the infiltration of innate and adaptive immune cells to the infected sites. The immunosuppressive protein indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme in the L-tryptophan-kynurenine metabolic pathway. Tryptophan depletion and tryptophan metabolites contribute to pathogen persistence by inhibiting T cell proliferation, inducing T cell apoptosis, and promoting the expansion of FOXP3(+) regulatory T (Treg) cells. We previously found that FOXP3(+) Treg cells are enriched in experimental lesions and that H. ducreyi induced IDO transcription in dendritic cells (DC) derived from blood of infected volunteers who developed pustules. Here, we showed that enzymatically active IDO was induced in DC by H. ducreyi. Neutralizing antibodies against interferon alpha/beta receptor 2 chain (IFNAR2) and tumor necrosis factor alpha (TNF-α) inhibited IDO induction. Inhibitors of the mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) also inhibited IDO expression. Neither bacterial contact with nor uptake by DC was required for IDO activation. H. ducreyi culture supernatant and H. ducreyi lipooligosaccharides (LOS) induced IDO expression, which required type I interferons, TNF-α, and the three MAPK (p38, c-Jun N-terminal kinase, and extracellular signal regulated kinase) and NF-κB pathways. In addition, LOS-induced IFN-β activated the JAK-STAT pathway. Blocking the LOS/Toll-like receptor 4 (TLR4) signaling pathway greatly reduced H. ducreyi-induced IDO production. These findings indicate that H. ducreyi-induced IDO expression in DC is largely mediated by LOS via type I interferon- and TNF-α-dependent mechanisms and the MAPK, NF-κB, and JAK-STAT pathways.

  15. Depletion of OLFM4 gene inhibits cell growth and increases sensitization to hydrogen peroxide and tumor necrosis factor-alpha induced-apoptosis in gastric cancer cells

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    Liu Rui-hua

    2012-04-01

    Full Text Available Abstract Background Human olfactomedin 4 (OLFM4 gene is a secreted glycoprotein more commonly known as the anti-apoptotic molecule GW112. OLFM4 is found to be frequently up-regulated in many types of human tumors including gastric cancer and it was believed to play significant role in the progression of gastric cancer. Although the function of OLFM4 has been indicated in many studies, recent evidence strongly suggests a cell or tissue type-dependent role of OLFM4 in cell growth and apoptosis. The aim of this study is to examine the role of gastric cancer-specific expression of OLFM4 in cell growth and apoptosis resistance. Methods OLFM4 expression was eliminated by RNA interference in SGC-7901 and MKN45 cells. Cell proliferation, anchorage-independent growth, cell cycle and apoptosis were characterized in vitro. Tumorigenicity was analyzed in vivo. The apoptosis and caspase-3 activation in response to hydrogen peroxide (H2O2 or tumor necrosis factor-alpha (TNF α were assessed in the presence or absence of caspase inhibitor Z-VAD-fmk. Results The elimination of OLFM4 protein by RNA interference in SGC-7901 and MKN45 cells significantly inhibits tumorigenicity both in vitro and in vivo by induction of cell G1 arrest (all P 2O2 or TNF α-induced apoptosis and caspase-3 activity (all P 2O2 or TNF α-induced apoptosis in OLFM4 knockdown cells (all P Conclusion Our study suggests that depletion of OLFM4 significantly inhibits tumorigenicity of the gastric cancer SGC-7901 and MKN45 cells. Blocking OLFM4 expression can sensitize gastric cancer cells to H2O2 or TNF α treatment by increasing caspase-3 dependent apoptosis. A combination strategy based on OLFM4 inhibition and anticancer drugs treatment may provide therapeutic potential in gastric cancer intervention.

  16. Expression of tumor necrosis factor-alpha-mediated genes predicts recurrence-free survival in lung cancer.

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    Baohua Wang

    Full Text Available In this study, we conducted a meta-analysis on high-throughput gene expression data to identify TNF-α-mediated genes implicated in lung cancer. We first investigated the gene expression profiles of two independent TNF-α/TNFR KO murine models. The EGF receptor signaling pathway was the top pathway associated with genes mediated by TNF-α. After matching the TNF-α-mediated mouse genes to their human orthologs, we compared the expression patterns of the TNF-α-mediated genes in normal and tumor lung tissues obtained from humans. Based on the TNF-α-mediated genes that were dysregulated in lung tumors, we developed a prognostic gene signature that effectively predicted recurrence-free survival in lung cancer in two validation cohorts. Resampling tests suggested that the prognostic power of the gene signature was not by chance, and multivariate analysis suggested that this gene signature was independent of the traditional clinical factors and enhanced the identification of lung cancer patients at greater risk for recurrence.

  17. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stimulates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins

    Science.gov (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  18. Tumor necrosis factor-alpha directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling.

    Science.gov (United States)

    Insulin resistant states are commonly associated with both increased circulating levels of tumor necrosis factor (TNF-a) and hepatic overproduction of very low density lipoproteins (VLDL). In the present study, we examined the potential mechanistic link between TNF-a and hepatic overproduction of ap...

  19. Tumor necrosis factor-alpha impairs hepatic insulin signaling and stumlates the overproduction of hepatic apolipoprotein B100-containing very low density lipoproteins

    Science.gov (United States)

    Mechanisms underlying hepatic overproduction of apolipoprotein B (apoB) 100-containing very low density lipoproteins (VLDL) in insulin resistance induced by tumor necrosis factor (TNF)-a were investigated. In the present study, we examined the potential role of TNF-a in insulin signaling and lipopro...

  20. Tumor necrosis factor alpha induces spermidine/spermine N1-acetyltransferase through nuclear factor kappaB in non-small cell lung cancer cells.

    Science.gov (United States)

    Babbar, Naveen; Hacker, Amy; Huang, Yi; Casero, Robert A

    2006-08-25

    Tumor necrosis factor alpha (TNFalpha) is a potent pleiotropic cytokine produced by many cells in response to inflammatory stress. The molecular mechanisms responsible for the multiple biological activities of TNFalpha are due to its ability to activate multiple signal transduction pathways, including nuclear factor kappaB (NFkappaB), which plays critical roles in cell proliferation and survival. TNFalpha displays both apoptotic and antiapoptotic properties, depending on the nature of the stimulus and the activation status of certain signaling pathways. Here we show that TNFalpha can lead to the induction of NFkappaB signaling with a concomitant increase in spermidine/spermine N(1)-acetyltransferase (SSAT) expression in A549 and H157 non-small cell lung cancer cells. Induction of SSAT, a stress-inducible gene that encodes a rate-limiting polyamine catabolic enzyme, leads to lower intracellular polyamine contents and has been associated with decreased cell growth and increased apoptosis. Stable overexpression of a mutant, dominant negative IkappaBalpha protein led to the suppression of SSAT induction by TNFalpha in these cells, thereby substantiating a role of NFkappaB in the induction of SSAT by TNFalpha. SSAT promoter deletion constructs led to the identification of three potential NFkappaB response elements in the SSAT gene. Electromobility shift assays, chromatin immunoprecipitation experiments and mutational studies confirmed that two of the three NFkappaB response elements play an important role in the regulation of SSAT in response to TNFalpha. The results of these studies indicate that a common mediator of inflammation can lead to the induction of SSAT expression by activating the NFkappaB signaling pathway in non-small cell lung cancer cells.

  1. Disruption of Early Tumor Necrosis Factor Alpha Signaling Prevents Classical Activation of Dendritic Cells in Lung-Associated Lymph Nodes and Development of Protective Immunity against Cryptococcal Infection

    Directory of Open Access Journals (Sweden)

    Jintao Xu

    2016-07-01

    Full Text Available Anti-tumor necrosis factor alpha (anti-TNF-α therapies have been increasingly used to treat inflammatory diseases and are associated with increased risk of invasive fungal infections, including Cryptococcus neoformans infection. Using a mouse model of cryptococcal infection, we investigated the mechanism by which disruption of early TNF-α signaling results in the development of nonprotective immunity against C. neoformans. We found that transient depletion of TNF-α inhibited pulmonary fungal clearance and enhanced extrapulmonary dissemination of C. neoformans during the adaptive phase of the immune response. Higher fungal burdens in TNF-α-depleted mice were accompanied by markedly impaired Th1 and Th17 responses in the infected lungs. Furthermore, early TNF-α depletion also resulted in disrupted transcriptional initiation of the Th17 polarization program and subsequent upregulation of Th1 genes in CD4+ T cells in the lung-associated lymph nodes (LALN of C. neoformans-infected mice. These defects in LALN T cell responses were preceded by a dramatic shift from a classical toward an alternative activation of dendritic cells (DC in the LALN of TNF-α-depleted mice. Taken together, our results indicate that early TNF-α signaling is required for optimal DC activation, and the initial Th17 response followed by Th1 transcriptional prepolarization of T cells in the LALN, which further drives the development of protective immunity against cryptococcal infection in the lungs. Thus, administration of anti-TNF-α may introduce a particularly greater risk for newly acquired fungal infections that require generation of protective Th1/Th17 responses for their containment and clearance.

  2. Tumor Necrosis Factor Alpha Inhibits L-Type Ca2+ Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway

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    Jorge Reyes-García

    2016-01-01

    Full Text Available Tumor necrosis factor alpha (TNF-α is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca2+ channel (L-VDCC current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S induced the same phenomenon. In tracheal myocytes from nonsensitized (NS and sensitized (S guinea pigs, an L-VDCC current (ICa was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF and a TNF-α receptor 1 (TNFR1 antagonist (WP9QY reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor nor actinomycin D (a transcription inhibitor showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway.

  3. The Possibility of Using Serum Concentrations of the Tumor Necrosis Factor-Alpha as a Biomarker in Mesial Temporal Lobe Epilepsy Associated With the Human Herpes Virus Neuroinfections

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    Yaroslav Ya. Nedopako

    2012-03-01

    Full Text Available In this study, mesial temporal lobe epilepsy (MTLE is shown to be associated with human herpes virus (HHV neuroinfections. We also demonstrate that the epileptic process is associated with an inflammatory reaction, and that the proinflammatory cytokine, the tumor necrosis factor-alpha (TNF-α is able to potentiate the reproduction of the herpesviruses. The study group (SG included 43 patients between 16 and 60 years with MTLE and HHV neuroinfections, diagnosed according to the PCR of the cerebrospinal fluid (CSF, serum or abnormal serum/CSF IgG ratio. The control group (CG included 20 patients of similar age with MTLE, but without the HHV neuroinfections. The concentration of TNF-α in the serum was determined by enzyme-linked immunosorbent assay ("VektorBEST" RF; N=0-50 pg/ml. Patients of the SG had high concentrations of TNF-α in serum (288±44.7 pg/ml, that were significantly higher than in the CG (p<0.05;Z

  4. Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects.

    Science.gov (United States)

    Beilfuss, Julia; Berg, Vivian; Sneve, Monica; Jorde, Rolf; Kamycheva, Elena

    2012-12-01

    Insufficient vitamin D status has been linked to autoimmune diseases, cancer and metabolic disorders, like obesity and insulin resistance. In vitro and animal studies suggest that vitamin D may play a crucial role in immune activation and inflammation. The relation between vitamin D and pro-inflammatory cytokines is not completely established. Furthermore, it is not known if the effect of vitamin D on entities of metabolic syndrome is mediated through its effect on cytokines or other biomarkers. The objectives of this study were to investigate if there is a relationship between vitamin D status and such pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and high sensitive C-reactive protein (hs-CRP) in patients with overweigh and obesity. We also proposed that the intervention with high dose of cholecalciferol may have effect on the cytokine levels and result in corresponding changes in the measures of insulin resistance (HOMA-IR and QUICKI). Serum levels of IL-6, TNF-α and hs-CRP were measured in 332 overweight and obese subjects who completed a 1-year randomised intervention with either 40,000 IU vitamin D (cholecalciferol) per week or 20,000 IU vitamin D per week, or placebo. We found significant associations between IL-6, TNF-α, vitamin D and insulin resistance indices at baseline. One year intervention with vitamin D decreased serum IL-6 levels; however hs-CRP levels were significantly increased. Neither measures of insulin resistance, nor TNF-α were influenced by a 1-year vitamin D supplementation.

  5. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis.

    Science.gov (United States)

    Krishnan, Asha; Stobaugh, Derrick J; Deepak, Parakkal

    2015-04-01

    The association between inhibition of tumor necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) and the onset of inflammatory bowel disease (IBD) is unclear. We sought to evaluate this association by analyzing adverse events (AEs) reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) with a standardized scoring tool for drug-induced AEs. A search of the FAERS for RA or JRA (January 2003-December 2011) reported with adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab was performed. This dataset was then queried for cases indicating IBD. Full-length reports were accessed using the Freedom of Information Act and organized by age, sex, concomitant medications, co-morbidities, type of TNF-α inhibitor used, and diagnosis/treatment details. The Naranjo score was used to determine whether the drug-induced AEs were definite, probable, possible, or doubtful. There were 158 cases of IBD after TNF-α inhibitor exposure in RA or JRA patients. Use of the Naranjo score revealed that, in a majority of the cases (71.5 %), TNF-α inhibitor exposure was considered a 'possible' cause. A majority of the 'probable cases' in JRA were reported with etanercept (40 patients, 90.91 %). There were no 'definite' cases of anti-TNF-induced IBD. After applying the Naranjo scale, a weak association between new-onset IBD and TNF-α inhibitor therapy in RA patients and a moderately strong association especially with etanercept exposure in JRA patients was observed. However, causality cannot be determined due to limitations of the FAERS and the Naranjo score.

  6. Dynamic distributions of tumor necrosis factor-alpha and its receptors in the red nucleus of rats with spared nerve injury.

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    Wang, Jing; Ding, Cui-Ping; Yu, Jing; Zeng, Xiao-Yan; Han, Shui-Ping; Wang, Jun-Yang

    2016-08-01

    Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-α) in the red nucleus (RN) plays a facilitated role in the development of neuropathic pain, and its effect is transmitted through TNF-α receptor (TNFR) subtypes 1 and 2. Here, the dynamic distributions of TNF-α and TNFRs in the RN of rats with spared nerve injury (SNI) were investigated. Western blot analysis and immunofluorescence staining indicated that TNF-α was hardly expressed in the RN of normal rats but significantly increased at 1 week and peaked at 2 weeks after SNI. Neurons and oligodendrocytes showed TNF-α expression at both 1 week and 2 weeks after SNI, while astrocytes and microglia produced TNF-α later than neurons and oligodendrocytes starting at 2 weeks after SNI. TNFR1 was constitutively expressed in the RN of normal rats and significantly enhanced at 2 weeks but not 1 week after SNI; it was mainly localized in neurons, oligodendrocytes and microglia. Astrocytes were not immunopositive for TNFR1 under normal conditions and at 1 week after injury, but small amounts of astrocytes showed TNFR1 expression at 2 weeks after SNI. A low level of TNFR2 was expressed in the RN of normal rats, but it was significantly increased at 1 week and 2 weeks after SNI and localized in neurons and all three types of glia. These findings suggest that neurons and three types of glia in the RN all contribute to TNF-α production and participate in the initiation and/or maintenance of neuropathic pain induced by SNI. TNF-α exerts its effects in different types of cells maybe through different receptors, TNFR1 and/or TNFR2, in the different stages of neuropathic pain.

  7. Promoter variants in interleukin-6 and tumor necrosis factor alpha and risk of coronary artery disease in a population from Western India

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    Aparna A Bhanushali

    2013-01-01

    Full Text Available Introduction: A central component of the atherosclerotic process is inflammation. Single nucleotide polymorphisms (SNPs present in the promoter region of various cytokines can lead to altered levels of the transcript and a state of low-grade inflammation exacerbating the risk of coronary artery disease (CAD. The present work tries to understand the role of permissive promoter variants in the interleukin-6 gene (IL-6-174G/C and the tumor necrosis factor alpha (TNFα-308G/A in the causation of CAD and also dyslipidemia. Materials and Methods: Genotyping was conducted on 100 cases of CAD and 150 controls by the allele termination assay SNaPshot. Biochemical parameters were determined by routine enzymatic endpoint methods. The results were analyzed by appropriate statistical methods. Results: No differences in the minor allele frequency IL-6-174G/C SNP were seen between cases and controls (0.13 vs. 0.12. The differences in the allele frequency of TNFα-308A between cases (6% and controls (2% have led to an odds ratio, 3.370; 95% confidence interval, 1.039-11.543; P=0.033 in the univariate analysis. In the final logistic regression analysis, however none of the variants were associated with an increased risk of CAD. Conclusions: In summary, no association of the permissive promoter variants in the IL-6 gene and the TNFα gene were seen with an increased CAD risk. These and other studies highlight the importance of doing population specific studies.

  8. Silencing tumor necrosis factor-alpha in vitro from small interfering RNA-decorated titanium nanotube array can facilitate osteogenic differentiation of mesenchymal stem cells.

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    Wang, Zhenlin; Hu, Zhiqiang; Zhang, Dawei; Zhuo, Mengchuan; Cheng, Jiwei; Xu, Xingping; Xing, Yongming; Fan, Jie

    2016-01-01

    Titanium implants are known for their bone bonding ability. However, the osseointegration may be severely disturbed in the inflammation environment. In order to enhance osseointegration of the implant in an inflamed environment, the small interfering RNA (siRNA) targeting tumor necrosis factor alpha (TNF-α) was used to functionalize titanium surface for gene silencing. The chitosan-tripolyphosphate-hyaluronate complexes were used to formulate nanoparticles (NPs) with siRNA, which were adsorbed directly by the anodized titanium surface. The surface characterization was analyzed by scanning electron microscope, atomic force microscopy, as well as contact angle measurement. The fluorescence microscope was used to monitor the degradation of the layer. The coculture system was established with mesenchymal stem cells (MSCs) grown directly on functionalized titanium surface and RAW264.7 cells (preactivated by lipopolysaccharide) grown upside in a transwell chamber. The transfection and knockdown efficiency of TNF-α in RAW264.7 cells were determined by fluorescence microscope, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. The cytoskeleton and osteogenic differentiation of MSCs were also analyzed. Regular vertical aligned nanotubes (~100 nm diameter and ~300 nm length) were generated after anodization of polished titanium. After loading with NPs, the nanotubes were filled and covered by a layer of amorphous particles. The surface topography changed and wettability decreased after covering with NPs. As expected, a burst degradation of the film was observed, which could provide sufficient NPs in the released supernatant and result in transfection and knockdown effects in RAW264.7 cells. The cytoskeleton arrangement of MSCs was elongated and the osteogenic differentiation was also significantly improved on NPs loading surface. In conclusion, the siRNA decorated titanium implant could simultaneously suppress inflammation and improve

  9. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha.

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    Jin, Xiaochun; Gereau, Robert W

    2006-01-04

    Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNFalpha can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNFalpha itself. However, the speed with which TNFalpha induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNFalpha may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNFalpha induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1(-/-) mice. In contrast, TNFalpha produced equivalent mechanical hypersensitivity in TRPV1(-/-) mice and wild-type littermates, suggesting a role for TRPV1 in TNFalpha-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na+ channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNFalpha on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNFalpha rapidly enhances TTX-resistant Na+ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNFalpha is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNFalpha is also significantly reduced by SB202190. These results suggest that TNFalpha may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation

  10. Effect of Helicobacter pylori and its virulence factors on portal hypertensive gastropathy and interleukin (IL-8, IL-10, and tumor necrosis factor-alpha levels

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    Zaigham Abbas

    2014-01-01

    Full Text Available Background/Aim: We aimed to assess the influence of Helicobacter pylori and its virulent factors, cytotoxin associated gene (cag A and E, on portal hypertensive gastropathy (PHG and the levels of interleukin (IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α. Patients and Methods: The patients with cirrhosis underwent screening endoscopy and the lesions related to PHG were graded. Biopsies were obtained for histology, and polymerase chain reaction (PCR of H. pylori 16S rRNA, cagA, cagE, and tissue cytokine levels was carried out. Absent or mild PHG was compared with moderate to severe PHG. Results: One hundred and forty patients with cirrhosis were studied; males numbered 92 and the mean age of the patients was 50.3 ± 12.0 years, H. pylori positivity in 87 (62.1% patients was associated with male gender (P = 0.032, younger age (P = 0.029, hepatitis D etiology (P = 0.005, higher serum albumin (0.000, lower Child Pugh score (P = 0.001, and lower portal vein diameter (P = 0.001. There was no significant difference in the levels of TNF-α and IL-8. However, a decrease in the anti-inflammatory cytokine IL-10 was noted with moderate to severe gastropathy. Four H. pylori strains were positive for both cagA and cagE, while four were positive for cagA only. All the four patients with both virulent factors had mild gastropathy only. Conclusion: The presence of H. pylori infection neither affected the severity of PHG nor augmented the IL-8 and TNF-α levels. There was a decline of virulent H. pylori strains and IL-10 levels in patients with advanced PHG.

  11. Combined use of serum adiponectin and tumor necrosis factor-alpha receptor 2 levels was comparable to 2-hour post-load glucose in diabetes prediction.

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    Yu-Cho Woo

    Full Text Available BACKGROUND: Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction. METHODS: We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS. Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2, interleukin-6 (IL-6, adipocyte-fatty acid binding protein (A-FABP and high-sensitivity C-reactive protein (hsCRP were measured in baseline samples. RESULTS: Seventy-six participants developed diabetes over 5.3 years (median. All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, "adiponectin + TNF-α R2" improved the area under ROC curve (AUC of the CDP model from 0.802 to 0.830 (P = 0.03, rendering its performance comparable to the "CDP + 2-hour post-OGTT glucose" model (AUC = 0.852, P = 0.30. A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2, had similar performance when added to the CDP model (AUC = 0.829 [95% CI: 0.808-0.849]. CONCLUSIONS: The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.

  12. Tumor Necrosis Factor Alpha Inhibits L-Type Ca(2+) Channels in Sensitized Guinea Pig Airway Smooth Muscle through ERK 1/2 Pathway.

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    Reyes-García, Jorge; Flores-Soto, Edgar; Solís-Chagoyán, Héctor; Sommer, Bettina; Díaz-Hernández, Verónica; García-Hernández, Luz María; Montaño, Luis M

    2016-01-01

    Tumor necrosis factor alpha (TNF-α) is a potent proinflammatory cytokine that plays a significant role in the pathogenesis of asthma by inducing hyperresponsiveness and airway remodeling. TNF-α diminishes the L-type voltage dependent Ca(2+) channel (L-VDCC) current in cardiac myocytes, an observation that seems paradoxical. In guinea pig sensitized tracheas KCl responses were lower than in control tissues. Serum from sensitized animals (Ser-S) induced the same phenomenon. In tracheal myocytes from nonsensitized (NS) and sensitized (S) guinea pigs, an L-VDCC current (ICa) was observed and diminished by Ser-S. The same decrease was detected in NS myocytes incubated with TNF-α, pointing out that this cytokine might be present in Ser-S. We observed that a small-molecule inhibitor of TNF-α (SMI-TNF) and a TNF-α receptor 1 (TNFR1) antagonist (WP9QY) reversed ICa decrease induced by Ser-S in NS myocytes, confirming the former hypothesis. U0126 (a blocker of ERK 1/2 kinase) also reverted the decrease in ICa. Neither cycloheximide (a protein synthesis inhibitor) nor actinomycin D (a transcription inhibitor) showed any effect on the TNF-α-induced ICa reduction. We found that CaV1.2 and CaV1.3 mRNA and proteins were expressed in tracheal myocytes and that sensitization did not modify them. In cardiac myocytes, ERK 1/2 phosphorylates two sites of the L-VDCC, augmenting or decreasing ICa; we postulate that, in guinea pig tracheal smooth muscle, TNF-α diminishes ICa probably by phosphorylating the L-VDCC site that reduces its activity through the ERK1/2 MAP kinase pathway.

  13. Effect of Helicobacter pylori and its Virulence Factors on Portal Hypertensive Gastropathy and Interleukin (IL)-8, IL-10, and Tumor Necrosis Factor-alpha Levels

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    Abbas, Zaigham; Yakoob, Javed; Usman, Muhammad W.; Shakir, Tanzila; Hamid, Saeed; Jafri, Wasim

    2014-01-01

    Background/Aim: We aimed to assess the influence of Helicobacter pylori and its virulent factors, cytotoxin associated gene (cag) A and E, on portal hypertensive gastropathy (PHG) and the levels of interleukin (IL)-8, IL-10, and tumor necrosis factor-alpha (TNF-α). Patients and Methods: The patients with cirrhosis underwent screening endoscopy and the lesions related to PHG were graded. Biopsies were obtained for histology, and polymerase chain reaction (PCR) of H. pylori 16S rRNA, cagA, cagE, and tissue cytokine levels was carried out. Absent or mild PHG was compared with moderate to severe PHG. Results: One hundred and forty patients with cirrhosis were studied; males numbered 92 and the mean age of the patients was 50.3 ± 12.0 years, H. pylori positivity in 87 (62.1%) patients was associated with male gender (P = 0.032), younger age (P = 0.029), hepatitis D etiology (P = 0.005), higher serum albumin (0.000), lower Child Pugh score (P = 0.001), and lower portal vein diameter (P = 0.001). There was no significant difference in the levels of TNF-α and IL-8. However, a decrease in the anti-inflammatory cytokine IL-10 was noted with moderate to severe gastropathy. Four H. pylori strains were positive for both cagA and cagE, while four were positive for cagA only. All the four patients with both virulent factors had mild gastropathy only. Conclusion: The presence of H. pylori infection neither affected the severity of PHG nor augmented the IL-8 and TNF-α levels. There was a decline of virulent H. pylori strains and IL-10 levels in patients with advanced PHG. PMID:24705150

  14. microRNA-142 is upregulated by tumor necrosis factor-alpha and triggers apoptosis in human gingival epithelial cells by repressing BACH2 expression

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    Li, Song; Song, Zhongchen; Dong, Jiachen; Shu, Rong

    2017-01-01

    Tumor necrosis factor-alpha (TNF-α) has been shown to cause apoptosis of gingival epithelial cells (GECs) in periodontitis. However, the underlying molecular mechanism is still unclear. In this study, we showed that miR-142 expression was significantly elevated in human GECs after exposure to TNF-α. Such induction was in a time- and concentration-dependent manner. Serum miR-142 levels were positively correlated with serum TNF-α levels in patients with chronic periodontitis (r = 0.314, P = 0.0152). Depletion of miR-142 was found to attenuate TNF-α-induced apoptosis, as determined by TUNEL staining and caspase-3 activity assays. In contrast, overexpression of miR-142 significantly reduced viability and induced apoptosis in GECs. Basic leucine zipper transcription factor 2 (BACH2) was identified to be a functional target of miR-142. Overexpression of miR-142 caused a 3-fold reduction of BACH2 protein in primary GECs. Overexpression of BACH2 significantly reversed miR-142- or TNF-α-induced apoptosis of GECs. Similar to the findings with miR-142 mimic, depletion of BACH2 significantly promoted apoptosis in GECs, which was accompanied by decreased expression of Bcl-2 and Bcl-xL and increased expression of Bax and Bim. Overall, miR-142 mediates TNF-α-induced apoptosis in gingival epithelial cells by targeting BACH2 and may represent a potential therapeutic target for periodontitis. PMID:28123644

  15. Synergistic effect of interferon-gamma and tumor necrosis factor-alpha on coxsackievirus and adenovirus receptor expression: an explanation of cell sloughing during testicular inflammation in mice.

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    Gao, Ying; Lui, Wing-Yee

    2014-03-01

    Coxsackievirus and adenovirus receptor (CAR) is a junction molecule that expresses on Sertoli and germ cells. It mediates Sertoli-germ cell adhesion and facilitates migration of preleptotene/leptotene spermatocytes across the blood-testis barrier, suggesting that CAR-based cell adhesion and migration are crucial for spermatogenesis. Interferon-gamma (IFNG) and tumor necrosis factor alpha (TNF) are two major cytokines that are elevated during testicular inflammation and cause reduced fertility. We investigated the mechanism by which IFNG and TNF exert their disruptive effects on testicular cell adhesion. We have demonstrated that combined treatment with IFNG and TNF (IFNG+TNF) exerts a synergistic effect by downregulating CAR mRNA and protein levels. Immunofluorescence staining revealed that IFNG+TNF treatment effectively removes CAR from the site of cell-cell contact. Using inhibitor and co-immunoprecipitation, we confirmed that IFNG+TNF mediates CAR protein degradation via ubiquitin-proteasome and NFKB pathways. Blockage of ubiquitin-proteasome pathway significantly inhibits CAR degradation, as indicated by the reappearance of CAR at the site of cell-cell contact. Additionally, IFNG+TNF reduces CAR mRNA via transcriptional regulation. Mutational studies have shown that IFNG+TNF-induced CAR repression is achieved by suppression of the basal transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays further confirmed that IFNG+TNF treament not only inhibits binding of the basal transcription factors but also promotes binding of NFKB subunits and Sp1 (negative regulators) to the CAR promoter region. Taken together, IFNG+TNF treatment significantly downregulates CAR expression, which provides an explanation of how cell sloughing in the epithelium mediates, by loss of CAR-based cell adhesion, during testicular inflammation.

  16. Effect of N-tosyl-L-phenylalanylchloromethyl Ketone on Tumor Necrosis Factor-alpha -induced NF-κB Activation and Apoptosis in U937 Cell Line

    Institute of Scientific and Technical Information of China (English)

    陈卫华; 陈燕; 崔国惠

    2004-01-01

    To investigate the effect of N-tosyl-L-phenylalanylchloromethyl ketone (TPCK) on tumor necrosis factor-alpha-induced NF-κB activation and apoptosis in U937 cell line, changes and subcellular localization of NF-κB/p65 and IκB-α were observed by fluorescencemicroscopy and expression and degradation of IκB-α by flow cytometry. The apoptosis of U937 cells was measured by flow cytometry and electrophoresis of DNA. Immunolfluorescence assay showed that NF-κB/p65,IκB-α only localized in cytoplasm. After TNF-α stimulation, p65 was localized only in nuclei, and IκB-α was only localized in cytoplasm and decreased. The changes of TNF-α stimulation were specifically inhibited by TPCK. Flow cytometry also revealed the downregulation of IκB-α protein during TNF-α-induced apoptosis and the down-regulation was specifically inhibited by TPCK. Flow cytometry also showed the apoptosis of U937 cells after TNF-α induction. DNA ladder can be detected in cells treated by TNF-α. It is concluded that degradation of IκB-α protein and NF-κB/p65 translocation occur during TNF-α-induced apoptosis of U937 cells, suggesting the activation of NF-κB.TPCK-sensitive protease plays an important role in the degradation of IκB-α protein induced by TNF-α in U937 cells. TPCK sensitive protease also plays an inportant role in the apoptosis of U937cells induced by TNF-α.

  17. Evaluation of leptin, interleukin-1 beta and tumor necrosis factor alpha in serum of malaria patients as prognostic markers of treatment outcome

    Institute of Scientific and Technical Information of China (English)

    Mariam Abdulrhman Al-Fadhli; Mohammad Ahmed Saraya; Jafar Abdulrida Qasem

    2014-01-01

    Objective: To analyze serum leptin levels in patients with malaria falciparum and compare them with healthy controls and correlate with development and outcome of malaria infection.Methods:healthy individuals of comparable age, racial and body mass index were taken as controls. All patients were diagnosed by clinical picture and the presence of malaria parasites in blood film. Estimation of liver function test, kidney function test, complete blood count, fasting blood sugar, fasting serum insulin, pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and interleukin 1 (IL1), estimation of morning serum leptin and calculation of body mass index (kg/m2) were done in both groups on the day of admission, on discharge and 7 d after discharge.Results:Sixty cases of malaria falciparum were included in this study as patients. Thirty while fasting serum insulin levels were not significantly different between the two groups. There were significant increases as regard to TNFα and IL1 in malaria patients. Significant differences were observed between the control and the patient group for leptin, TNFα and IL1 at the time of admission and discharge. After discharge for 7 d, a significant decline in serum leptin levels, TNFα and IL1 in the patients group was observed as compared with time of admission and time of discharge, a positive correlation between serum leptin levels and TNFα and IL1. At admission, leptin levels were significantly higher in patients group than in control Conclusions: Leptin hormone level might play an important role in development and outcome of malaria infection.

  18. Blockade of Tumor Necrosis Factor-Alpha: A Role for Adalimumab in Neovascular Age-Related Macular Degeneration Refractory to Anti-Angiogenesis Therapy

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    Beatriz Fernández-Vega

    2016-03-01

    Full Text Available Aims: To report a case of wet age-related macular degeneration (wet-AMD refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF therapy in a patient who showed visual and anatomical improvement and stabilization after starting a subcutaneous treatment course with adalimumab, an anti-tumor necrosis factor-alpha (TNF-α drug, for concomitant Crohn's disease. Methods: Observational case report of a female patient. Ophthalmological evaluation was performed by slit lamp and ophthalmoscopy (posterior pole and anterior segment. Best-corrected visual acuity (BCVA was determined, and imaging was performed by fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT. Intravitreal therapies used and treatment with anti-TNF-α were recorded. Results: A 64-year-old woman with wet-AMD was treated with fourteen intravitreal injections of ranibizumab (0.5 mg for a period of 40 months with intervals of 1-6 months. She initially showed a good visual and anatomical response to periodic anti-VEGF treatment but during check visits, anatomical and functional responses deteriorated. At the 40-month follow-up, the patient had developed Crohn's disease, and her rheumatologist started treatment with adalimumab (40 mg subcutaneously every 2 weeks. During the 25 months of treatment with adalimumab, the patient did not require any additional intravitreal anti-VEGF treatments because her BCVA, clinical, and OCT findings improved and remained stable. Conclusions: We described a case of a patient with wet-AMD refractory to anti-VEGF therapy, which clinically benefited from subcutaneous adalimumab therapy. Treatment with subcutaneous anti-TNF-α in combination with anti-VEGF therapy avoids the high cost and risks related to multiple intravitreal anti-VEGF injections with good functional and anatomic outcomes.

  19. A comprehensive study of tumor necrosis factor-alpha genetic polymorphisms, its expression in skin and relation to histopathological features in psoriasis

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    Nikhil N Moorchung

    2015-01-01

    Full Text Available Background: Tumor necrosis factor-alpha (TNFα is an important inflammatory mediator in psoriasis and several genetic polymorphisms of this cytokine have been reported. Majority of studies have focused on the increased G- A polymorphism at the -308 position in psoriasis. There has been no comprehensive study evaluating the genetic polymorphisms, TNFα expression in the skin and histopathology. We are undertaking this study to outline TNFα genetic polymorphisms, its skin expression and histopathological correlation to help determine its role at the genetic and protein level. Materials and Methods : 112 patients of psoriasis and 243 healthy controls were included in this prospective study. 5 ml of peripheral blood was collected to study the TNFα genetic polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Histopathological analysis of biopsies from the 112 patients were done using visual analogue scale and correlated with the findings. 61 of these cases were analyzed for TNFα expression by immunohistochemistry. The results of study were statistically analyzed using SPSS 13.0 statistical package program. Results: A strong association of TNFα -308 G/A polymorphism in psoriasis cases was detected. The A allele of the TNFα -308 G/A polymorphism occurs rarely in the Indian population, however there is an over representation of this allele in psoriatic patients. There was no association seen between TNFα genotype and histopathological severity of psoriasis. Conclusion: The study emphasized the central role of TNFα in the pathogenesis of psoriasis. TNFα genotyping may be helpful in identifying subjects in whom anti-TNFα therapeutic strategies may be tried.

  20. A20 overexpression under control of mouse osteocalcin promoter in MC3T3-E1 cells inhibited tumor necrosis factor-alpha-induced apoptosis

    Institute of Scientific and Technical Information of China (English)

    Yue-juan QIN; Zhen-lin ZHANG; Lu-yang YU; Jin-wei HE; Ya-nan HOU; Tian-jin LIU; Jia-cai WU; Song-hua WU; Li-he GUO

    2006-01-01

    Aim: To construct an A20 expression vector under the control of mouse osteocalcin promoter (OC-A20), and investigate osteoblastic MC3T3-E1 cell line, which stably overexpresses A20 protein prevented tumor necrosis factor (TNF)-alpha-induced apoptosis. Methods: OC-A20 vector was constructed by fusing a fragment of the mouse osteocalcin gene-2 promoter with human A20 complementary DNA. Then the mouse MC3T3-E1 cell line, stably transfected by A20, was established. The expression of A20 mRNA and A20 protein in the cells were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To determine the specificity of A20 expression in osteoblast, the mouse osteoblastic MC3T3-E1 cell line and mouse embryo fibro-blast NIH3T3 cell line were transiently transfected with OC-A20. The anti-apoptotic role of A20 in MC3T3-E1 cells was determined by Flow cytometric analysis (FACS), terminal dUTP nick endo-labeling (TUNEL) and DNA gel electrophoresis analysis (DNA Ladder), respectively. Results: Weak A20 expression was found in MC3T3-El cells with the primers of mouse A20. A20 mRNA and A20 protein expression were identified in MC3T3-E1 cells transfected with OC-A20 using RT-PCR and Western blot analysis. Only A20 mRNA expression was found in MC3T3-E1 cell after MC3T3-E1 cells and NIH3T3 cells were transient transfected with OC-A20. A decrease obviously occurred in the rate of apoptosis in the OC-A20 group compared with the empty vector (pcDNA3) group by FACS (P<0.001). A significant increase in TUNEL positive staining was found in the pcDNA group compared with OC-A20 group (P<0.001). Simultaneously, similar effects were demonstrated in DNA gel electrophoresis analysis. Conclusion: We constructed an osteoblast-specific expression vector that expressed A20 protein in MC3T3-E1 cells and confirmed that A20 protects osteoblast against TNF-alpha-induced apoptosis.

  1. Silencing tumor necrosis factor-alpha in vitro from small interfering RNA-decorated titanium nanotube array can facilitate osteogenic differentiation of mesenchymal stem cells

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    Wang Z

    2016-07-01

    Full Text Available Zhenlin Wang,1,* Zhiqiang Hu,2,* Dawei Zhang,3 Mengchuan Zhuo,1 Jiwei Cheng,1 Xingping Xu,1 Yongming Xing,1 Jie Fan2 1Department of Orthopaedics, 2Department of Otorhinolaryngology, No 113 Hospital of PLA, Ningbo, 3Department of Orthopaedics, Xijing Hospital of PLA, Xi’an, People’s Republic of China *These authors contributed equally to this work Abstract: Titanium implants are known for their bone bonding ability. However, the osseointegration may be severely disturbed in the inflammation environment. In order to enhance osseointegration of the implant in an inflamed environment, the small interfering RNA (siRNA targeting tumor necrosis factor alpha (TNF-α was used to functionalize titanium surface for gene silencing. The chitosan–tripolyphosphate–hyaluronate complexes were used to formulate nanoparticles (NPs with siRNA, which were adsorbed directly by the anodized titanium surface. The surface characterization was analyzed by scanning electron microscope, atomic force micro­scopy, as well as contact angle measurement. The fluorescence microscope was used to monitor the degradation of the layer. The coculture system was established with mesenchymal stem cells (MSCs grown directly on functionalized titanium surface and RAW264.7 cells (preactivated by lipopolysaccharide grown upside in a transwell chamber. The transfection and knockdown efficiency of TNF-α in RAW264.7 cells were determined by fluorescence microscope, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. The cytoskeleton and osteogenic differentiation of MSCs were also analyzed. Regular vertical aligned nanotubes (~100 nm diameter and ~300 nm length were generated after anodization of polished titanium. After loading with NPs, the nanotubes were filled and covered by a layer of amorphous particles. The surface topography changed and wettability decreased after covering with NPs. As expected, a burst degradation of the film was observed, which

  2. The allelic distribution of -308 Tumor Necrosis Factor-alpha gene polymorphism in South African women with cervical cancer and control women

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    Williamson Anna-Lise

    2006-01-01

    Full Text Available Abstract Background Cervical cancer is due to infection with specific high-risk types of human papillomavirus (HPV. Although the incidence of genital HPV infection in various population groups is high, most of these regress without intervention. Investigating genetic host factors and cellular immune responses, particularly cytokines, could help to understand the association between genital HPV infection and carcinogenesis. The tumor necrosis factor alpha (TNF-α cytokine plays an important role in all stages of cervical cancer and has the ability to induce the regression of human tumors. Therefore the aim of the study was to investigate the allelic distribution of -308 TNF-α gene polymorphism in South African women with cervical cancer compared to control women. Methods Included in our study were women with histologically proven cancer of the cervix (n = 244 and hospital-based controls (n = 228. All patients and controls were from mixed race and black population groups in South Africa. The detection of a bi-allelic -308 (A/G polymorphism in the promoter region of TNF-α was investigated using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR technique. The distributions of the allelic frequencies were stratified in both patients and controls into two South African ethnic population groups. Results In this study we observed no association between the distribution of -308 TNF-α polymorphism and the risk of developing cervical cancer even after combining the data from the two ethnic populations (X2 = 2.26. In addition, using the chi-squared test we found no significant association between the known risk factors for cervical cancer and the allele distribution of -308 TNF-α. However, the frequency of the rare high-producing allele -308A of TNF-α was significantly lower in the South African population when compared to Caucasians and Chinese population groups. Conclusion We demonstrated no association between -308 TNF

  3. The correlations among serum tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and sialic acids with peripheral lymphocytes in bovine tropical theileriosis.

    Science.gov (United States)

    Razavi, Seyed Mostafa; Nazifi, Saeed; Emadi, Mahboobeh; Rakhshandehroo, Ehsan

    2010-10-01

    The infection with protozoan parasite Theileria annulata induces changes triggering the activation and/or proliferation of the host lymphocytes. In order to find out the possible correlations among peripheral circulatory lymphocytes, cytokine activities and the level of sialic acids, 50 dairy Holstein cattle, naturally infected with T. annulata, were divided into 4 subgroups according to their parasitemia rates (5%). Also, ten non-infected cattle were sampled as control group. Blood samples were taken from jugular vein into acid citrate dextrose-containing tubes for measuring hematological parameters and B and T (CD(4) and CD(8)) cell populations and without anticoagulant for TNF-alpha, IFN-gamma and sialic acid concentrations. Remarkable decreases observed in red blood cells (RBCs), white blood cells (WBCs) and packed cell volume (PCV) in infected cattle compared to healthy ones (P < 0.05). Also, with increase in parasitemia rate, total lymphocytes and monocytes alleviated in the diseased groups. By contrast, total neutrohpils and the concentrations of TNF-alpha, IFN-gamma and total sialic acids were significantly elevated (P < 0.05) in infected animals. Accordingly, the circulatory populations of CD(4) and CD(8) T cells and B cells showed a substantial decrease, while a significant increase was observed in T (CD(4) and CD(8)) cells in cattle infected with <1% parasitemia rates. Decreased circulatory T cell population shows the ineffective responses of T cells to the stimulatory cytokines such as IFN-gamma or TNF-alpha. On the other hand, the elevation of cytokines (particularly IFN-gamma) and sialic acids have presumably an inhibitory role on circulatory B cell population in infected cattle. In addition, a high level of sialic acid concentration indicates the probable role of sialic acid to regulate the parasite-host cell adhesion during sporozoites invasion.

  4. A study on biochemical facet of anemia in cancers: A strong link between erythropoietin and tumor necrosis factor alpha in anemic cancer patients

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    P Kalyani

    2015-01-01

    Full Text Available Background: The three direct factors that could lead cancer patients to anemia, apart from therapy are iron deficiency, inflammatory cytokines surge and decreased erythropoietin (Epo. Our aim was to quantify biochemical and hematologic markers serum Epo, ferritin (Fe and tumor necrosis factor-alpha (TNF-α along with hemoglobin (Hb to understand the associations between these factors, patient characteristics and anemia. Materials And Methods: The study group consisted of 100 anemic cancer patients and 80 controls. Biochemical marker levels were determined by the enzyme linked immunosorbent assay on an autoanalyser. Univarient analysis, t-test, ANOVA, Bonferroni test, linear regression was performed to find correlations and associations among various factors. Results: The baseline serum Epo (153.07 ± 173.88 vs. 23.607 ± 36.462 and Fe levels (233.53 ± 257.12 vs. 23.06 ± 20.04 were adequately high in cases compared with that controls (P ≤ 0.001. Considerable raise in TNF-α levels was also observed (16.26 ± 13.44 vs. 11.2375 ± 4.84 (P = 0.001. TNF-α correlated positively (P = 0.022 with Epo and Fe (P = 0.000, which was also evident from large effect size of Epo (r2 = 0.414, TNF-α (r2 = 0.369, Hb (r2 = 0.226. Epo and Hb were negatively correlated (β = −0.375, P = 0.001 and Epo production was found to be appropriate for the degree of anemia (O/P ratio of 3.51 ± 1.26 vs. 1.43 ± 0.47. A strong association was seen between Hb, Epo and TNF-α in hematological and gynecological malignancies for different grades of anemia. Men were more prone to life-threatening anemia (13% than women (9%. Conclusion: Anemia in cancers was not because of inadequate Epo or Fe levels, but because of improper Epo response. Further studies on molecular analysis of Epo, biochemical and molecular interplay between Epo and TNF-α could explain a rationale for anemia in cancers.

  5. Soluble endoglin, transforming growth factor-Beta 1 and soluble tumor necrosis factor alpha receptors in different clinical manifestations of preeclampsia.

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    Luiza O Perucci

    Full Text Available BACKGROUND: Despite intensive research, the etiopathogenesis of preeclampsia (PE remains uncertain. Inflammatory and angiogenic factors are thought to play considerable roles in this disease. The objective of this study was to investigate the association between soluble endoglin (sEng, transforming growth factor beta-1 (TGF-β1 and tumor necrosis factor alpha soluble receptors (sTNF-Rs and the clinical manifestations of PE. METHODS: Plasma levels of sEng, TGF-β1 and sTNF-Rs were determined by ELISA in 23 non-pregnant, 21 normotensive pregnant and 43 PE women. PE women were stratified into subgroups according to the severity [mild (n = 12 and severe (n = 31] and onset-time of the disease [early (n = 19 and late (n = 24]. RESULTS: Pregnancy was associated with higher levels of sEng, sTNF-R1 and sTNF-R2 than the non-pregnant state. Moreover, PE women had higher levels of sEng and sTNF-R1 than normotensive pregnant women. No difference was found in TGF-β1 levels, comparing the three study groups. Late PE had higher levels of sTNF-R1 and sTNF-R2 than early PE. No significant differences were found in sEng and TGF-β1 comparing early and late PE. sEng levels were higher in severe PE than in mild PE and no difference was found for TGF-β1, sTNF-R1 and sTNF-R2 levels. There was a positive correlation among sEng, TNF-R1 and sTNF-2 levels. Logistic regression analysis revealed that primiparity and sEng levels are independently associated with the development of PE. Furthermore, sEng levels are independently associated with the disease severity. CONCLUSIONS: These results suggest that pregnancy is a condition associated with higher levels of anti-angiogenic and pro-inflammatory factors than the non-pregnant state and that PE is associated with an imbalance of these factors in the maternal circulation.

  6. Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients

    Institute of Scientific and Technical Information of China (English)

    Roba M. Talaat; Ahmed A. Esmail; Reda Elwakil; Adel A. Gurgis; Mahmoud I. Nasr

    2012-01-01

    Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV).The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure.We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection.To test this.hypothesis,we investigated the role of the polymorphism -308G/A,which is located in the promoter region of the TNF-α gene,in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR).The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease.Our results showed that at the TNF-α -308 position,the G/G allele was most common (78.5%) in the study population,with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%,respectively).Frequencies of G/G,G/A,and A/A genotypes were 87%,7%,and 6% in patients with liver cirrhosis and were 94%,4%,and 2% in patients with HCC,respectively.Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls,indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α.The serum level of TNF-α was positively correlated with HCV infection.Taken together,these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection,but may be an independent risk factor for HCC.

  7. Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients.

    Science.gov (United States)

    Paredes-Turrubiarte, Gabriela; González-Chávez, Antonio; Pérez-Tamayo, Ruy; Salazar-Vázquez, Beatriz Y; Hernández, Vito S; Garibay-Nieto, Nayeli; Fragoso, José Manuel; Escobedo, Galileo

    2016-05-01

    Morbid obesity has been shown to increase the risk to develop hepatic steatosis, also referred to as non-alcoholic fatty liver disease (NAFLD). Emerging evidence suggests that the severity of NAFLD may associate with increased serum levels of inflammatory markers as well as decreased concentration of mediators with anti-inflammatory actions, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL) 10, respectively. We thus examined the serum levels of TNF-α and IL-10 in 102 morbidly obese women and men (body mass index > 40 kg/m(2)), exhibiting different grades of NAFLD. Blood glucose, glycated hemoglobin, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, triglycerides, high- and low-density lipoproteins, parameters of liver function, TNF-α, and IL-10 were measured in each subject. The stage of NAFLD was estimated by abdominal ultrasound imaging. In comparison with morbidly obese subjects without steatosis, morbidly obese patients with NAFLD showed increased age (39.23 ± 9.80 years), HOMA-IR (6.74 ± 1.62), total cholesterol (219.7 ± 9.58 mg/dl), aspartate aminotransferase (36.25 ± 3.24 UI/l), gamma-glutamyl transpeptidase (37.12 ± 3.41 UI/l), and TNF-α (37.41 ± 1.72 pg/ml) as well as decreased serum levels of IL-10 (61.05 ± 2.43 pg/ml). Interestingly, the systemic levels of TNF-α increased, while IL-10 decreased in accordance with the severity of NAFLD, which supports a role for systemic inflammatory mediators in promoting steatosis progression. Further clinical prospective studies need to be addressed to elucidate the role of TNF-α and IL-10 in the development of NAFLD while also establishing their clinical utility in the assessment of morbidly obese patients at higher risk to develop severe steatosis.

  8. Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor alpha in obese women.

    Science.gov (United States)

    Polak, Jan; Klimcakova, Eva; Moro, Cedric; Viguerie, Nathalie; Berlan, Michel; Hejnova, Jindriska; Richterova, Blanka; Kraus, Ivan; Langin, Dominique; Stich, Vladimir

    2006-10-01

    Adipocytokines secreted by adipose tissue are suggested to play a role in the development of obesity-related complications. Regular aerobic exercise has been shown to reduce the risk of metabolic complications in obese subjects. The aim of this study was to investigate the effect of aerobic training on gene expression in subcutaneous abdominal adipose tissue (SCAAT) and on plasma levels of several adipocytokines in obese women. Twenty-five obese sedentary premenopausal women (body mass index, 32.18 +/- 3.17 kg/m(2)) underwent a 12-week aerobic exercise program, with a frequency of 5 d/wk and intensity corresponding to 50% of individual maximal oxygen consumption (V(.-)(O(2)max)) consisting of 2 sessions per week of supervised aerobic exercise and 3 sessions per week of home-based exercise on a bicycle ergometer. Before and after the aerobic training, (V(.-)(O(2)max)) and body composition were measured and plasma and SCAAT biopsy samples (in a subgroup of 8 subjects) were obtained for determination of plasma and messenger RNA levels of adipocytokines (leptin, adiponectin, interleukin 6, tumor necrosis factor alpha). The aerobic training resulted in an increase of subjects' V o(2)max by 12.8% (24.6 +/- 3.9 vs 27.7 +/- 4.8 mL x min(-1) x kg(-1), P < .05). Body weight and fat mass were reduced by 5.9% (88.5 +/- 8.2 vs 83.3 +/- 7.7 kg, P < .001) and 6.4% (38.8 +/- 4.2% vs 36.3 +/- 4.6%, P < .001), respectively, and the revised QUantitative Insulin sensitivity ChecK Index (QUICKI) increased (0.43 +/- 0.06 vs 0.48 +/- 0.06, P < .05) during the aerobic training. No aerobic training-induced changes in messenger RNA levels of the investigated genes in SCAAT were observed. A decrease of plasma leptin (24.3 +/- 8.7 vs 18.1 +/- 8.3 ng/mL, P < .05) was detected, whereas plasma levels of other cytokines remained unchanged. In moderately obese females, 3 months' aerobic training did not promote changes in the adipose tissue gene expression or plasma levels of the adipocytokines

  9. Interleukin-6 and tumor necrosis factor alpha in synovial fluid are associated with progression of radiographic knee osteoarthritis in subjects with previous meniscectomy

    DEFF Research Database (Denmark)

    Larsson, S; Englund, M; Struglics, A

    2015-01-01

    concentrations of interleukin (IL)-6, -8 and tumor necrosis factor (TNF)-α by multiplex immunoassay, graded radiographic features of tibiofemoral and patellofemoral OA according to the Osteoarthritis Research Society International (OARSI) atlas, scored patient-reported outcomes using the Knee Injury.......07-2.09) in the preceding years. Subjects with increasing concentrations of IL-6 or TNF-α between examinations were five times more likely to have progressed in joint space narrowing between the same examinations, as compared to those with stable or decreasing concentrations (OR 5.17; 1.54-17.32 and 5.01; 1...

  10. Suspected de novo Hepatitis B in a Patient Receiving Anti-Tumor Necrosis Factor Alpha Therapy for the Treatment of Crohn's Disease

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    Tetsuya Ishida

    2014-01-01

    Full Text Available We report a 45-year-old female patient who developed acute hepatic disorder during anti-tumor necrosis factor α therapy for the treatment of Crohn's disease (CD. She was diagnosed as colonic CD and placed on infliximab (IFX. She was negative for hepatitis B surface antigen at the initiation of IFX therapy, but developed acute hepatitis after the 30th administration of IFX 4 years and 1 month after the first administration. She was suspected to have had occult hepatitis B virus infection before IFX therapy, and de novo hepatitis B was considered the most likely diagnosis. Hepatitis subsided after discontinuation of anti-tumor necrosis factor α therapy and initiation of treatment with entecavir. She started to receive adalimumab to prevent relapse of CD. She has continued maintenance therapy with entecavir and adalimumab and has since been asymptomatic. As de novo hepatitis B may be fatal, virological testing for hepatitis B is essential for patients who are being considered for treatment that may weaken the immune system.

  11. Single nucleotide polymorphisms in the tumor necrosis factor-alpha gene promoter region alter the risk of psoriasis vulgaris and psoriatic arthritis: a meta-analysis.

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    Junqing Zhu

    Full Text Available BACKGROUND: It has been confirmed that tumor necrosis factor-alpha (TNFα, a macrophage-derived pro-inflammatory cytokine, plays an important role in the pathogenesis of psoriasis vulgaris and psoriatic arthritis (PsV&PsA. In contrast, the reported association of TNFα gene promoter region single nucleotide polymorphisms (SNPs and PsV&PsA has remained controversial. Accordingly, we performed a meta-analysis to provide new evidence that SNPs in the TNFα gene promoter region alter not only the risk of psoriasis vulgaris (PsV or psoriatic arthritis (PsA but also of PsV&PsA. METHODS: Interrelated literature dated to October 2012 was acquired from the PubMed, ScienceDirect, and SpringerLink databases. The number of the genotypes and/or alleles for the TNFα promoter in the PsV and PsA and control subjects was obtained. Odds ratios (ORs and 95% confidence intervals (CIs were used to calculate the risk of PsV and/or PsA with TNFα promoter SNPs. RESULTS: A total of 26 papers of 2159 for PsV (2129 normal controls and 2360 for PsA (2997 normal controls were included in our meta-analysis. The results showed that the variant genotype and allele of TNFα -308A/G was protective in pooled groups of patients with PsV&PsA (OR = 0.682, 0.750; 95% CI, 0.596-0.779, 0.653-0.861. However, the variant genotypes and alleles of TNFα -238A/G and -857T/C had an increased risk of PsV&PsA (OR = 2.493, 2.228, 1.536, 1.486, 95% CI, 1.777-3.498, 1.628-3.049, 1.336-1.767, 1.309-1.685. Moreover, the meta-analysis revealed a significant association between TNFα -238A/G and -857T/C polymorphism and PsA susceptibility (OR = 2.242, 2.052, 1.419, 1.465; 95% CI, 1.710-2.941, 1.614-2.610, 1.214-1.658, 1.277-1.681. In contrast, the variant genotypes and alleles of TNFα -308A/G proved to be protective against PsV (OR = 0.574, 0.650, 95% CI, 0.478-0.690, 0.556-0.759, whereas TNFα -238A/G was found to have a risk association (OR = 2.636, 2.223, 95% CI, 1.523-4.561, 1

  12. Inhibition of tumor necrosis factor-alpha-induced interleukin-6 expression by telmisartan through cross-talk of peroxisome proliferator-activated receptor-gamma with nuclear factor kappaB and CCAAT/enhancer-binding protein-beta.

    Science.gov (United States)

    Tian, Qingping; Miyazaki, Ryohei; Ichiki, Toshihiro; Imayama, Ikuyo; Inanaga, Keita; Ohtsubo, Hideki; Yano, Kotaro; Takeda, Kotaro; Sunagawa, Kenji

    2009-05-01

    Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

  13. El factor de necrosis de los tumores o caquectina

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    Jorge Eliécer Ossa Londoño

    1988-02-01

    Full Text Available

    Se presenta una revisión de la literatura sobre el Factor de Necrosis de los Tumores o Caquectina, con base en artículos publicados durante los anos 1986-1987, haciendo hincapié en las diferencias funcionales y moleculares entre el FNT Alfa, la Linfotoxina o FNT Beta y la Caquectina. Se enfatizan los mecanismos del shock, de la necrosis tumoral y de la caquexia; se Indican las propiedades antitumorales del FNT in vivo e in vitro y se esbozan esquemas terapéuticos experimentales que permiten colegir que el FNT tendrá un papel Importante en la Inmunoterapia del cáncer en el hombre.

    This is a review of the 1986-1987 Literature on the Tumor Necrosis Factor (TNF or Cachectin, emphasizing functional and molecular differences among TNF alpha, Iymphotoxin or TNF beta and Cachectin. Mechanisms of shock, tumor necrosis and cachexia are discussed. In vivo and ín vítro antitumoral properties of TNF are indicated, as well as some experimental therapeutic regimens. These facts allow the suggestion that TNF might become an Important aid for Immunotherapy of cancer In humans.

  14. Mathematical Modeling of Melanoma Cell Migration with an Elastic Continuum Model for the Evaluation of the Influence of Tumor Necrosis Factor-Alpha on Migration

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    Julia Vianna Gallinaro

    2013-01-01

    Full Text Available An elastic continuum mathematical model was implemented to study collective C8161 melanoma cell migration during a “scratch wound” assay, in control and under the influence of the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α. The model has four constants: force that results from lamellipod formation (F, adhesion constant between cells and extracellular matrix (ECM (b, cell layer elasticity modulus (k, and growth rate (ρ. A nonlinear regression routine was used to obtain the parameters of the model with data from an experiment made with C8161 melanoma cells, with and without TNF-α. Coefficient of determination for both situations was R2=0.89 and R2=0.92, respectively. The parameters values obtained were similar to the ones found in the literature. However, the adhesion constant value decreased with the introduction of TNF-α, which is not in accordance with expected since the presence of TNF-α is associated with an increased expression of integrins that would promote an enhanced adhesion among cells. The model was used in a study relating to the adhesion constant and cell migration, and the results suggested that cell migration decreases with higher adhesion, which is also not in accordance with expected. These differences would not occur if it was considered that TNF-α increases the elasticity modulus of the cell layer.

  15. Microglia-derived proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta induce Purkinje neuronal apoptosis via their receptors in hypoxic neonatal rat brain.

    Science.gov (United States)

    Kaur, Charanjit; Sivakumar, Viswanathan; Zou, Zhirong; Ling, Eng-Ang

    2014-01-01

    The developing cerebellum is extremely vulnerable to hypoxia which can damage the Purkinje neurons. We hypothesized that this might be mediated by tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) derived from activated microglia as in other brain areas. One-day-old rats were subjected to hypoxia following, which the expression changes of various proteins in the cerebellum including hypoxia inducible factor-1α, TNF-α, IL-1β, TNF-R1 and IL-1R1 were analyzed. Following hypoxic exposure, TNF-α and IL-1β immunoexpression in microglia was enhanced coupled by that of TNF-R1 and IL-1R1 in the Purkinje neurons. Along with this, hypoxic microglia in vitro showed enhanced release of TNF-α and IL-1β whose receptor expression was concomitantly increased in the Purkinje neurons. In addition, nitric oxide (NO) level was significantly increased in the cerebellum and cultured microglia subjected to hypoxic exposure. Moreover, cultured Purkinje neurons treated with conditioned medium derived from hypoxic microglia underwent apoptosis but the incidence was significantly reduced when the cells were treated with the same medium that was neutralized with TNF-α/IL-1β antibody. We conclude that hypoxic microglia in the neonatal cerebellum produce increased amounts of NO, TNF-α and IL-1β which when acting via their respective receptors could induce Purkinje neuron death.

  16. Association of-238G/A polymorphism of tumor necrosis factor-alpha gene promoter region with outcomes of hepatitis B virus infection in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    Liang-Ping Lu; Xing-Wang Li; Ying Liu; Guo-Chang Sun; Xue-Ping Wang; Xi-Lin Zhu; Quan-You Hu; Hui Li

    2004-01-01

    AIM: To clarify whether -238G/A polymorphism of tumor necrosis factor-α (TNF-α) gene promoter region was associated with outcomes of hepatitis B virus (HBV) infection in Han population of northem China, and to analyze the geneenvironment interaction between -238G/A polymorphism and cigarette smoking or alcohol consumption.METHODS: A case-control study was conducted to analyze the association of TNF-α gene promoter polymorphism with HBV infection outcomes. A total of 207 patients with chronic hepatitis B (HB) and 148 cases of self-limited HBV infection from Ditan Hospital and Shunyi District Hospital in Beijing,respectively were recruited. History of smoking and alcohol drinking was inquired by a questionnaire. The -238G/A polymorphism of TNF-α gene promoter was genotyped by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP).RESULTS: The frequencies of GG and GA genotypes were 98.07% and 1.93% in chronic HB patients and 93.24% and 6.76% in self-limited HBV infection individuals, respectively (x2=5.30, P=0.02). The frequency of G allele was significantly higher in patients with chronic HB that in individuals with self-limited HBV infection (99.03% vs 96.62%, x2=5.20,P=0.02). Only modestly increased risk of onset of chronic HB was found in smokers (OR=1.40, 95% CI: 0.87-2.28,P=0.14) and drinkers (OR=1.26, 95%CI: 0.78-2.05, P=0.32).There was a positive interaction between genotype GG and cigarette smoking with an interaction index (Ⅱ) of 2.95, or alcohol consumption with an Ⅱ of 1.64.CONCLUSION: The -238G/A polymorphism of TNF-α gene promoter region is independently associated with different outcomes of HBV infection.

  17. Different effect of glutamine on macrophage tumor necrosis factor-alpha release and heat shock protein 72 expression in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Mengfan Liang; Xuemin Wang; Yuan Yuan; Quanhong Zhou; Chuanyao Tong; Wei Jiang

    2009-01-01

    Macrophage plays a vital role in sepsis. However, the modulatory effect of glutamine (Gln) on macrophage/ monocyte-mediate cytokines release is still controver-sial. Thus, we investigated the effect of Gin on macro-phage tumor necrosis factor (TNF)-α release and heat shock protein (HSP) 72 expression in vivo and in vitro. Data from our study indicated that the increase of HSP72 expression was significant at 8 mM of Gln 4 h after lipopolysaccharide (LPS) stimulation and became independent of Gin concentrations at 24 h, whereas TNF-α release was dose- and time-dependent on Gln. Heat stress (HS) induced more HSP72 and less TNF-α production compared with the non-HS group. However, the production of TNF-α in cells pretreated with HS was increased with increasing concentrations of Gln. Treatment with various concentrations of Gin for 1 h and then 0.5 mM Gin for 4h led to an increase in HSP72 expression, but not in TNF-α production. In sepsis model mice, Gin treatment led to a significantly lower intracellular TNF-α level and an increase in HSP72 expression in mouse peritoneal macrophages. Our results demonstrate that Gin directly increases TNF-α release of LPS-stimulated RAW264.7 macro-phages in a dose-dependent manner, and also decreases mouse peritoneal macrophages TNF-α release in the sepsis model. Taken together, our data suggest that there may be more additional pathways by which Gln modulates cytokine production besides HSP72 expression in macrophage during sepsis.

  18. Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Muller glia proliferation during zebrafish retinal regeneration.

    Science.gov (United States)

    Nelson, Craig M; Ackerman, Kristin M; O'Hayer, Patrick; Bailey, Travis J; Gorsuch, Ryne A; Hyde, David R

    2013-04-10

    Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Müller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator of transcription 3 (Stat3) transcription factors and re-enter the cell cycle to yield undifferentiated neuronal progenitors that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis of light-damaged retinal homogenates, which induced Müller glia proliferation when injected into an undamaged eye, revealed increased expression of tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα expression initially increased in apoptotic photoreceptors and later in Müller glia. Morpholino-mediated knockdown of TNFα expression before light damage diminished the expression of both Ascl1a and Stat3 in Müller glia and significantly reduced the number of proliferating Müller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Müller glia resulted in fewer proliferating Müller glia, suggesting that Müller glial-derived TNFα recruited additional Müller glia to re-enter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary for TNFα expression in Müller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also exhibited increased TNFα expression that was required for Müller glia proliferation. Thus, TNFα is the first molecule identified that is produced by dying retinal neurons and is necessary to induce Müller glia to proliferate in the zebrafish retinal regeneration response.

  19. Tumor necrosis factor-alpha is produced by dying retinal neurons and is required for Müller glia proliferation during zebrafish retinal regeneration

    Science.gov (United States)

    Nelson, Craig M.; Ackerman, Kristin M.; O’Hayer, Patrick; Bailey, Travis J.; Gorsuch, Ryne A.; Hyde, David R.

    2013-01-01

    Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Müller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator of transcription 3(Stat3) transcription factors and reenter the cell cycle to yield undifferentiated neuronal progenitors that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis of light-damaged retinal homogenates, which induced Müller glia proliferation when injected into an undamaged eye, revealed increased expression of Tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα expression initially increased in apoptotic photoreceptors and later in Müller glia. Morpholino-mediated knockdown of TNFα expression prior to light damage diminished the expression of both Ascl1a and Stat3 in Müller glia and significantly reduced the number of proliferating Müller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Müller glia resulted in fewer proliferating Müller glia, suggesting that Müller glial-derived TNFα recruited additional Müller glia to reenter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary for TNFα expression in Müller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also exhibited increased TNFα expression that was required for Müller glia proliferation. Thus, TNFα is the first molecule identified that is produced by dying retinal neurons and is necessary to induce Müller glia to proliferate in the zebrafish retinal regeneration response. PMID:23575850

  20. Application of Structural-Dynamic Approaches Provide Novel Insights Into the Enzymatic Mechanism of the Tumor Necrosis Factor-Alpha Converting Enzyme (TACE)

    Energy Technology Data Exchange (ETDEWEB)

    Sagi, I.; Milla, M

    2008-01-01

    Zinc dependent metalloproteinases comprise a large family of structurally homologous enzymes with a wide variety of biological roles. Originally described as proteinases involved in extracellular matrix (ECM) catabolism, these enzymes were later found to serve major roles as initiators of signaling pathways in many aspects of biology, ranging from cell proliferation, differentiation and communication, to pathological states associated with tumor metastasis, inflammation, tissue degeneration and cell death. From these enzymes, the tumor necrosis factor-a converting enzyme (TACE) stands out as a central shedding activity mediating the regulated release of a host of cytokines, receptors and other cell surface molecules. Selective drugs targeted at blocking TACE for treatment of rheumatoid arthritis and other disease indications are highly sought. Yet, the structural and chemical knowledge underlying its enzymatic activity is very limited. This is in part due to the fact that the catalytic zinc atom of metalloproteinases is usually spectroscopically silent and hence difficult to study using conventional spectroscopic and analytical tools. Most structural and biochemical studies, as well as medicinal chemistry efforts carried out so far were limited to non-dynamic structure/function characterization. Thus, to date, our mechanistic knowledge comes from theoretical calculations derived from static crystal structures from family members that are highly similar in their amino acid sequence and three-dimensional structure.This review introduces the importance of real-time quantification of biophysical properties and structural kinetic behavior applied to the study of TACE and other zinc metalloproteinases to dissect their molecular mechanisms. The molecular details that link the catalytic chemistry to key kinetic, electronic and structural events have remained elusive because of the difficulties associated with probing time-dependent structure-function aspects of enzymatic

  1. DEVELOPMENT OF ALOPECIA DURING TREATMENT WITH A TUMOR NECROSIS FACTOR-ALPHA INHIBITOR IN A FEMALE PATIENT WITH PSORIATIC ARTHRITS: A CLINICAL CASE

    Directory of Open Access Journals (Sweden)

    R. G. Mukhina

    2016-01-01

    Full Text Available Objective: to describe a case of the total development of alopecia in a female patient with psoriatic arthritis during treatment with a tumor necrosis factor-αlpha (TNF-α inhibitor. Materials and methods. Patient I., aged 36 years has been followed up at the Kazan’ Center of Rheumatic Diseases and Osteoporosis since 1998. At approximately the same time, the patient noted the appearance of skin eruptions behind the ears, on the skin of the scalp. She was examined by a dermatologist who diagnosed psoriasis. In 2005, she was admitted to Kazan’ Rheumatology Center, City Clinical Hospital Seven, for the development of obvious synovitis of the knee joint and for the inefficiency of therapy with nonsteroidal anti-inflammatory drugs and diagnosed with psoriatic arthritis. During the prescribed therapy with methotrexate 10 mg/week, evident menstrual irregularities were observed in the patient who stopped using the drug herself. The second pregnancy occurred in 2008. Articular syndrome progression and eruptive psoriasis were recorded in the lactation period. After lactation cessation in 2009, she was hospitalized again. Her examination revealed high laboratory activity (erythrocyte sedimentation rate, as high as 40 mm/hr; magnetic resonance imaging of the knee joints showed the signs of bilateral synovitis; lumbar spine radiography exhibited grade II sacroiliitis. Leflunomide 20 mg/day was recommended as a basic drug. In 2012, the patient used leflunomide, her condition worsened; joint pain progressed; new joints were involved into the process, and cutaneous manifestations were aggravated. To verify a diagnosis and to choose therapy, the patient was referred to a consultation at the Moscow Research Institute of Rheumatology. Results. In connection with the high activity of the disease and with no response to the performed therapy, it was recommended to initiate therapy with biologics, such as infliximab, the drug of choice. Seven infliximab

  2. Experimental Study on Inhibitory Effect of Niacinamide on Tumor Necrosis Factor-alpha-induced Matrix Degradation of Annulus Fibrous Tissue in vitro

    Institute of Scientific and Technical Information of China (English)

    Runbing XU; Zengwu SHAO; Liming XIONG

    2008-01-01

    Summary: The inhibitory effect of niacinamide on tumor necrosis factor-α (TNF-α) induced annulus fibrous (AF) degradation was assessed, and the mechanism of the inhibition was investigated. Chiba's intervertebral disc (IVD) culture model was established. Forty-eight IVDs from 12 adult Japanese white rabbits were randomly divided into 4 groups (12 IVDs in each group), and various concentrations of niacinamide and TNF-α were added to the medium for intervention: negative control group, niacinamide control group (0.5 mg/mL niacinamide), degeneration group (10 ng/mL TNF-α), and treatment group (0.5 mg/mL niacinamide and 10 ng/mL TNF-α). After one week's culture, AFs were collected for glycosaminoglycan (GS) content measurement, safranin O-fast green staining, and immunohistochemical staining for typeⅠ,Ⅱ collagen and cysteine containing aspartate specific protease-3 (Caspase-3). It was found that the GS content in treatment group was increased by about 48% as compared with degeneration group (t=16.93, P<0.001), and close to that in niacinamide control group (r=0.71, P=0.667). Safranine O-fast green staining exhibited higher staining density and better histological structure of AF in the treatment group as compared with the degeneration group. Immunohistochemical staining for both Type Ⅰ and Ⅱ collagen demonstrated that lameilar structure and continuity of collagen in treatment group were better reserved than in degeneration group. Positive staining rate of Caspase-3 in AFs of negative control group, niacinamide control group, degeneration group and treatment group was 3.4%, 4.3%, 17.9% and 10.3% respectively. The positive rate in treatment group was significantly lower than in degeneration group (P<0.01). It was concluded that niacinamide could effectively alleviate TNF-α induced destruction and synthesis inhibition of matrix ingredients in AFs. The inhibition may be related with reduction of expression of Caspase-3. Thus, niacinamide is of potential for

  3. Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum urticae dioicae foliorum.

    Science.gov (United States)

    Obertreis, B; Ruttkowski, T; Teucher, T; Behnke, B; Schmitz, H

    1996-04-01

    An extract of Urtica dioica folium (IDS 23, Rheuma-Hek), monographed positively for adjuvant therapy of rheumatic diseases and with known effects in partial inhibition of prostaglandin and leukotriene synthesis in vitro, was investigated with respect to effects of the extract on the lipopolysaccharide (LPS) stimulated secretion of proinflammatory cytokines in human whole blood of healthy volunteers. In the assay system used, LPS stimulated human whole blood showed a straight increase of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) secretion reaching maximum concentrations within 24 h following a plateau and slight decrease up to 65 h, respectively. The concentrations of these cytokines was strongly positively correlated with the number of monocytes/macrophages of each volunteer. TNF-alpha and IL-1 beta concentration after LPS stimulation was significantly reduced by simultaneously given IDS 23 in a strictly dose dependent manner. At time 24 h these cytokine concentrations were reduced by 50.8% and 99.7%, respectively, using the highest test IDS 23 assay concentration of 5 mg/ml (p < 0.001). After 65 h the corresponding inhibition was 38.9% and 99.9%, respectively (p < 0.001). On the other hand IDS 23 showed no inhibition but stimulated IL-6 secretion in absence of LPS alone. Simultaneously given LPS and IDS 23 resulted in no further increase. In contrast to described effects on arachidonic acid cascade in vitro, tested Urtica dioica phenol carbon acid derivates and flavonoides such as caffeic malic acid, caffeic acid, chlorogenic acid, quercetin and rutin did not influence LPS stimulated TNF-alpha, IL-1 beta and IL-6 secretion in tested concentrations up to 5 x 10(-5) mol/l. These further findings on the pharmacological mechanism of action of Urticae dioica folia may explain the positive effects of this extract in the treatment of rheumatic diseases.

  4. Tumor necrosis factor (TNF)-alpha-induced IL-8 expression in gastric epithelial cells: role of reactive oxygen species and AP endonuclease-1/redox factor (Ref)-1.

    Science.gov (United States)

    O'Hara, Ann M; Bhattacharyya, Asima; Bai, Jie; Mifflin, Randy C; Ernst, Peter B; Mitra, Sankar; Crowe, Sheila E

    2009-06-01

    TNF-alpha contributes to oxidative stress via induction of reactive oxygen species (ROS) and pro-inflammatory cytokines. The molecular basis of this is not well understood but it is partly mediated through the inducible expression of IL-8. As redox factor-1 (Ref-1), is an important mediator of redox-regulated gene expression we investigated whether ROS and Ref-1 modulate TNF-alpha-induced IL-8 expression in human gastric epithelial cells. We found that TNF-alpha treatment of AGS cells enhanced nuclear expression of Ref-1 and potently induced IL-8 expression. Overexpression of Ref-1 enhanced IL-8 gene transcription at baseline and after TNF-alpha treatment whereas Ref-1 suppression and antioxidant treatment inhibited TNF-alpha-stimulated IL-8 expression. TNF-alpha-mediated enhancement of other pro-inflammatory chemokines like MIP-3 alpha and Gro-alpha was also regulated by Ref-1. Although TNF-alpha increased DNA binding activity of Ref-1-regulated transcription factors, AP-1 and NF-kappaB, to the IL-8 promoter, promoter activity was mainly mediated by NF-kappaB binding. Silencing of Ref-1 in AGS cells inhibited basal and TNF-alpha-induced AP-1 and NF-kappaB DNA binding activity, but not their nuclear accumulation. Collectively, we provide the first mechanistic evidence of Ref-1 involvement in TNF-alpha-mediated, redox-sensitive induction of IL-8 and other chemokines in human gastric mucosa. This has implications for understanding the pathogenesis of gastrointestinal inflammatory disorders.

  5. Ketamine inhibits tumor necrosis factor-alpha and interleukin-6 gene expressions in lipopolysaccharide-stimulated macrophages through suppression of toll-like receptor 4-mediated c-Jun N-terminal kinase phosphorylation and activator protein-1 activation.

    Science.gov (United States)

    Wu, Gone-Jhe; Chen, Ta-Liang; Ueng, Yune-Fang; Chen, Ruei-Ming

    2008-04-01

    Our previous study showed that ketamine, an intravenous anesthetic agent, has anti-inflammatory effects. In this study, we further evaluated the effects of ketamine on the regulation of tumor necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6) gene expressions and its possible signal-transducing mechanisms in lipopolysaccharide (LPS)-activated macrophages. Exposure of macrophages to 1, 10, and 100 microM ketamine, 100 ng/ml LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. A concentration of 1000 microM of ketamine alone or in combined treatment with LPS caused significant cell death. Administration of LPS increased cellular TNF-alpha and IL-6 protein levels in concentration- and time-dependent manners. Meanwhile, treatment with ketamine concentration- and time-dependently alleviated the enhanced effects. LPS induced TNF-alpha and IL-6 mRNA syntheses. Administration of ketamine at a therapeutic concentration (100 microM) significantly inhibited LPS-induced TNF-alpha and IL-6 mRNA expressions. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA into macrophages decreased cellular TLR4 levels. Co-treatment of macrophages with ketamine and TLR4 siRNA decreased the LPS-induced TNF-alpha and IL-6 productions more than alone administration of TLR4 siRNA. LPS stimulated phosphorylation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos from the cytoplasm to nuclei. However, administration of ketamine significantly decreased LPS-induced activation of c-Jun N-terminal kinase and translocation of c-Jun and c-Fos. LPS increased the binding of nuclear extracts to activator protein-1 consensus DNA oligonucleotides. Administration of ketamine significantly ameliorated LPS-induced DNA binding activity of activator protein-1. Therefore, a clinically relevant concentration of ketamine can inhibit TNF-alpha and IL-6 gene expressions in LPS-activated macrophages. The suppressive mechanisms occur through

  6. Expressão local do fator de necrose tumoral alfa na ruptura prematura de membranas Local expression of tumor necrosis factor-alpha on premature rupture of membranes

    Directory of Open Access Journals (Sweden)

    Valquíria Roveran

    2009-05-01

    Full Text Available OBJETIVO: comparar a expressão do fator de necrose tumoral alfa (TNF-α em membranas ovulares com ruptura prematura (RPM e com ruptura oportuna das mesmas; verificar a associação entre a expressão do TNF-α em membranas ovulares e o grau de corioamnionite das mesmas e correlacionar a expressão do TNF-α e o tempo de ruptura das membranas. MÉTODOS: foram analisadas as membranas ovulares de 31 parturientes com RPM, com idade gestacional acima de 34 semanas, e de 14 parturientes com ruptura oportuna das membranas, com idade gestacional igual ou maior de 37 semanas. A detecção da corioamnionite foi feita por meio de estudo histopatológico. A avaliação da expressão do TNF-α foi feita por meio de técnica imunoistoquímica, na qual foi empregado o método streptavidina-biotina-peroxidase (LSAB. RESULTADOS: o tempo médio de ruptura foi de 16,6 horas. A frequência da expressão de TNF-α, nos Grupos Controle e Estudo, não mostrou diferença significante (χ2=6,6; p=0,08. No Grupo Estudo, houve correlação entre o grau de corioamnionite e a intensidade da expressão de TNF-α (coeficiente de Spearman (Rs=0,4; p=0,02. CONCLUSÕES: não houve diferença significante entre as expressões do TNF-α em membranas ovulares com ruptura prematura e com ruptura oportuna das mesmas; no Grupo Estudo, constatou-se associação significante entre a expressão do TNF-α e o grau de corioamnionite e não houve associação entre o tempo de ruptura e a intensidade da expressão do TNF-α.PURPOSE: to compare the expression of tumor necrosis factor-alpha (TNF-α in ovular membranes with premature rupture (MPR and with opportune rupture; to verify the association between the expression of the TNF-α in ovular membranes and the degree of chorioamnionitis, correlating the expression of the TNF-α and the membranes' time of rupture. METHODS: ovular membranes from 31 parturients with MPR, with gestational ages over 34 weeks, and from parturients with opportune

  7. Tumor necrosis factor-alpha upregulates 11beta-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-beta in HepG2 cells.

    Science.gov (United States)

    Ignatova, Irena D; Kostadinova, Radina M; Goldring, Christopher E; Nawrocki, Andrea R; Frey, Felix J; Frey, Brigitte M

    2009-02-01

    The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11beta-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-alpha increases 11beta-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11beta-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-alpha, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-alpha-induced transcription of the 11beta-HSD1 gene (HSD11B1) in HepG2 cells. We found that TNF-alpha acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-alpha in the proximal promoter region (-180 to +74). Cotransfection with human CCAAT/enhancer binding protein-alpha (C/EBPalpha) and C/EBPbeta-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBPalpha, but also C/EBPbeta, in basal and only of C/EBPbeta in the TNF-alpha-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPbeta on the proximal HSD11B1 promoter upon TNF-alpha treatment. In conclusion, C/EBPalpha and C/EBPbeta control basal transcription, and TNF-alpha upregulates 11beta-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPbeta to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-alpha-mediated 11beta-HSD1 regulation, and that TNF-alpha stimulates enzyme activity in vivo.

  8. The role of tumor necrosis factor-alpha and interleukin-1 in the mammalian testis and their involvement in testicular torsion and autoimmune orchitis

    Directory of Open Access Journals (Sweden)

    Lysiak Jeffrey J

    2004-03-01

    Full Text Available Abstract This review will focus the roles of TNF-alpha, IL-1 alpha, and IL-1 beta in the mammalian testis and in two testicular pathologies, testicular torsion and orchitis. TNF alpha in the testis is produced by round spermatids, pachytene spermatocytes, and testicular macrophages. The type 1 TNF receptor has been found on Sertoli and Leydig cells and numerous studies suggest a paracrine mode of action for TNF alpha in the normal testis. IL-1 alpha has been reported to be produced by Sertoli cells, testicular macrophages, and possibly postmeiotic germ cells. IL-1 receptors have been reported on Sertoli cells, Leydig cells, testicular macrophages, and germ cells suggesting both autocrine and paracrine functions. While these proinflammatory cytokines have important roles in normal testicular homeostasis, an elevation of their expression can lead to testicular dysfunctions. Testicular torsion is a clinical pathology with results in testicular ischemia and surgical intervention is often required for reperfusion. A pivotal role for IL-1beta in the pathology of testicular torsion has been recently described whereby an increase in IL-1beta production after reperfusion of the testis is correlated with the activation of the stress-related kinase, c-jun N-terminal kinase, and ultimately resulting in neutrophil recruitment to the testis and germ cell apoptosis. In autoimmune orchitis, on the other hand, TNF alpha produced by T-lymphocytes and macrophages of the testis has been implicated in the development and progression of the disease. Thus, both proinflammatory cytokines, TNF alpha and IL-1, have significant roles in normal testicular functions as well as in certain testicular pathologies.

  9. DNA from protozoan parasites Babesia bovis, Trypanosoma cruzi, and T. brucei is mitogenic for B lymphocytes and stimulates macrophage expression of interleukin-12, tumor necrosis factor alpha, and nitric oxide.

    Science.gov (United States)

    Shoda, L K; Kegerreis, K A; Suarez, C E; Roditi, I; Corral, R S; Bertot, G M; Norimine, J; Brown, W C

    2001-04-01

    The activation of innate immune responses by genomic DNA from bacteria and several nonvertebrate organisms represents a novel mechanism of pathogen recognition. We recently demonstrated the CpG-dependent mitogenic activity of DNA from the protozoan parasite Babesia bovis for bovine B lymphocytes (W. C. Brown, D. M. Estes, S. E. Chantler, K. A. Kegerreis, and C. E. Suarez, Infect. Immun. 66:5423-5432, 1998). However, activation of macrophages by DNA from protozoan parasites has not been demonstrated. The present study was therefore conducted to determine whether DNA from the protozan parasites B. bovis, Trypanosoma cruzi, and T. brucei activates macrophages to secrete inflammatory mediators associated with protective immunity. DNA from Escherichia coli and all three parasites stimulated B-lymphocyte proliferation and increased macrophage production of interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO). Regulation of IL-12 and NO production occurred at the level of transcription. The amounts of IL-12, TNF-alpha, and NO induced by E. coli and protozoal DNA were strongly correlated (r2 > 0.9) with the frequency of CG dinucleotides in the genome, and immunostimulation by DNA occurred in the order E. coli > or = T. cruzi > T. brucei > B. bovis. Induction of inflammatory mediators by E. coli, T. brucei, and B. bovis DNA was dependent on the presence of unmethylated CpG dinucleotides. However, at high concentrations, E. coli and T. cruzi DNA-mediated macrophage activation was not inhibited following methylation. The recognition of protozoal DNA by B lymphocytes and macrophages may provide an important innate defense mechanism to control parasite replication and promote persistent infection.

  10. Combined anti-tumor necrosis factor-alpha therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone

    NARCIS (Netherlands)

    Edwards, C.K., 3rd; Green, J.S.; Volk, H.D.; Schiff, M.; Kotzin, B.L.; Mitsuya, H.; Kawaguchi, T.; Sakata, K.M.; Cheronis, J.; Trollinger, D.; Bankaitis-Davis, D.; Dinarello, C.A.; Norris, D.A.; Bevilacqua, M.P.; Fujita, M.; Burmester, G.R.

    2012-01-01

    Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA) may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs) or anti-TNF-alpha therapy

  11. Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system

    DEFF Research Database (Denmark)

    Taupin, V; Renno, T; Bourbonnière, L

    1997-01-01

    /microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF-alpha in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin...

  12. Plasma L-cystine/L-glutamate imbalance increases tumor necrosis factor-alpha from CD14+ circulating monocytes in patients with advanced cirrhosis.

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    Eiji Kakazu

    Full Text Available BACKGROUND AND AIMS: The innate immune cells can not normally respond to the pathogen in patients with decompensated cirrhosis. Previous studies reported that antigen-presenting cells take up L-Cystine (L-Cys and secrete substantial amounts of L-Glutamate (L-Glu via the transport system Xc- (4F2hc+xCT, and that this exchange influences the immune responses. The aim of this study is to investigate the influence of the plasma L-Cys/L-Glu imbalance observed in patients with advanced cirrhosis on the function of circulating monocytes. METHODS: We used a serum-free culture medium consistent with the average concentrations of plasma amino acids from patients with advanced cirrhosis (ACM, and examined the function of CD14+ monocytes or THP-1 under ACM that contained 0-300 nmol/mL L-Cys with LPS. In patients with advanced cirrhosis, we actually determined the TNF-alpha and xCT mRNA of monocytes, and evaluated the correlation between the plasma L-Cys/L-Glu ratio and TNF-alpha. RESULTS: The addition of L-Cys significantly increased the production of TNF alpha from monocytes under ACM. Monocytes with LPS and THP-1 expressed xCT and a high level of extracellular L-Cys enhanced L-Cys/L-Glu antiport, and the intracellular GSH/GSSG ratio was decreased. The L-Cys transport was inhibited by excess L-Glu. In patients with advanced cirrhosis (n = 19, the TNF-alpha and xCT mRNA of monocytes were increased according to the Child-Pugh grade. The TNF-alpha mRNA of monocytes was significantly higher in the high L-Cys/L-Glu ratio group than in the low ratio group, and the plasma TNF-alpha was significantly correlated with the L-Cys/L-Glu ratio. CONCLUSIONS: A plasma L-Cys/L-Glu imbalance, which appears in patients with advanced cirrhosis, increased the TNF-alpha from circulating monocytes via increasing the intracellular oxidative stress. These results may reflect the immune abnormality that appears in patients with decompensated cirrhosis.

  13. Lipopolysaccharide (LPS) stimulates the production of tumor necrosis factor (TNF)-alpha and expression of inducible nitric oxide synthase (iNOS) by osteoclasts (OCL) in murine bone marrow cell culture.

    Science.gov (United States)

    Kikkawa, I; Saito, S; Tominaga, K; Hoshino, Y; Ooi, Y; Nakano, M

    1998-01-01

    Osteoclasts (OCL) resorb bone. They are essential for the development of normal bones and the repair of impaired bones. The function of OCL is presumed to be supported by cytokines and other biological mediators, including tumor necrosis factor (TNF)-alpha and nitric oxide (NO). Bacterial lipopolysaccharide (LPS) is a potent inducer of TNF-alpha and inducible nitric oxide synthase (iNOS), which is the specific enzyme for synthesizing NO from L-arginine. To obtain direct evidence on LPS-induced TNF-alpha production and iNOS expression by OCL, OCL-enriched cultures were prepared by 7-day cocultures of bone marrow cells of adult BALB/c mice and osteoblastic cells (OBs) derived from calvaria of newborn BALB/c mice, and the generation of TNF-alpha and iNOS in OCL stimulated with LPS was examined immunocytochemically. When the cultured cells were stimulated with 100 ng/ml of LPS, OCL clearly showed TNF-alpha and iNOS expression. Without LPS-stimulation, no expression was observed. TNF activity in the culture supernatants of the OCL-enriched cultures in the presence of LPS was also detected by cytotoxic assay that used TNF-sensitive L929 cells. The dentin resorption activity of OCL was estimated by area and number of pits formed on dentin slices, which were covered by the OCL fraction and cultured in the presence or absence of LPS, sodium nitroprusside (SNP; a NO generating compound), N(G)-monomethyl L-arginine acetate (L-NMMA; a competitive inhibitor of NO synthase (NOS)), or LPS plus L-NMMA. Pit formation was obviously inhibited in the presence of SNP and slightly inhibited in the presence of L-NMMA, but it was not affected in the presence of LPS or LPS plus L-NMMA. These findings indicate that OCL produces TNF and expresses iNOS in response to LPS, but the LPS-activation of OCL scarcely affects pit formation by them.

  14. Níveis de interleucina-6 e fator de necrose tumoral-alfa no liquor de recém-nascidos a termo com encefalopatia hipóxico-isquêmica Levels of interleukin-6 and tumor necrosis factor-alpha in the cerebrospinal fluid of full-term newborns with hypoxic-ischemic encephalopathy

    Directory of Open Access Journals (Sweden)

    Rita de Cássia Silveira

    2003-08-01

    Full Text Available OBJETIVO: avaliar os níveis liquóricos de IL-6 e TNF-alfa em recém-nascidos a termo com encefalopatia hipóxico-isquêmica (EHI, comparando-os com os de recém-nascidos controles. METODOLOGIA: estudo caso-controle realizado no período de julho de 1999 a outubro de 2001, incluindo dois grupos de recém-nascidos a termo: controle, com 20 recém-nascidos sem sepse e/ou meningite e com escore de Apgar > 9 no primeiro e quinto minutos de vida; e casos, com 15 recém-nascidos asfixiados, caracterizados pelo escore de Apgar 3,0 mmol/l e necessidade de ventilação com pressão positiva pelo menos durante 2 minutos após o nascimento. Foram coletadas amostras de liquor nas primeiras 48 horas de vida, para determinação dos níveis de IL-6 e TNF-alfa pelo método de enzimoimunoensaio. RESULTADOS: os grupos não diferiram quanto ao peso de nascimento, idade gestacional, classificação quanto ao peso e idade gestacional, tipo de parto e tempo médio de obtenção do liquor; seus exames foram obtidos em média com 17 horas de vida. Nos recém-nascidos asfixiados, as medianas dos níveis liquóricos foram: 157,5 pg/ml para IL-6 e 14,7 pg/ml para TNF-alfa, significativamente mais elevadas que nos controles (IL-6: 4,1 pg/ml e TNF-alfa: 0,16 pg/ml. CONCLUSÕES: recém-nascidos a termo com EHI apresentaram níveis liquóricos de IL-6 e TNF-alfa mais elevados que controles, possivelmente devido à produção local cerebral dessas citocinas, especialmente o TNF-alfa. Estes achados estimulam estudos futuros, utilizando bloqueadores cerebrais das ações dessas citocinas como estratégia de neuroproteção.OBJECTIVE: to determine cerebrospinal fluid levels of interleukin-6 and tumor necrosis factor-alpha in full-term infants with hypoxic-ischemic encephalopathy, comparing with control infants. METHODS: controlled, prospective study, performed between July 1999 and October 2001 with two groups of full-term newborns: 20 controls with no sepsis and/or meningitis

  15. Association of Obesity and Breast Cancer Risk: The Role of Estrogen, Tumor Necrosis Factor-alpha, and Adiponectin as Risk factors (preliminary study

    Directory of Open Access Journals (Sweden)

    Ampi Retnowarnadi

    2009-04-01

    Full Text Available BACKGROUND: Breast cancer is the most frequent cancer diagnosed among women. Many factors influence the carcinogenesis of breast cancer. The aim of this study to analyze the role of obesity (waist circumference and body mass index, serum Estradiol levels, TNF-α, and Adiponectin in the occurrence of breast cancer. METHODS: This was observational study with case control design. Eleven breast cancer patients as cases and twelve Fibroadenoma Mammae (FAM patients as controls were analyzed. The serum Estrogen, TNF-α and Adiponectin were examined in their association with breast cancer risk. RESULTS: Women with breast tumor and waist circumference >80 cm have significantly higher breast cancer risk than women with breast tumor and waist circumference 2.30 pg/ml have higher breast cancer risk (19.25 times than women with breast tumor and have lower serum TNF-α levels (95% CI=1.77-209.55, p=0.015. Whereas, women with breast tumor and lower Adiponectin/TNF-α ratio (80 cm and low Adiponectin/TNF-α ratio in women with breast tumor are significantly associated with an increased risk for breast cancer. KEYWORDS: obesity, breast cancer, adiponectin/TNF-α ratio.

  16. Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha priming.

    Science.gov (United States)

    Romieu-Mourez, Raphaëlle; François, Moïra; Abate, Amanda; Boivin, Marie-Noëlle; Birman, Elena; Bailey, Dana; Bramson, Jonathan L; Forner, Kathy; Young, Yoon-Kow; Medin, Jeffrey A; Galipeau, Jacques

    2010-10-15

    It is unknown whether mesenchymal stromal cells (MSC) can regulate immune responses targeting tumor autoantigens of low immunogenicity. We tested here whether immunization with MSC could break immune tolerance towards the ErbB-2/HER-2/neu tumor antigen and the effects of priming with IFN-γ and tumor necrosis factor-α (TNF-α) on this process. BALB/c- and C57BL/6-derived MSC were lentivirally transduced to express a kinase-inactive rat neu mutant (MSC/Neu). Immunization of BALB/c mice with nontreated or IFN-γ-primed allogeneic or syngeneic MSC/Neu induced similar levels of anti-neu antibody titers; however, only syngeneic MSC/Neu induced protective neu-specific CD8(+) T cell responses. Compared to immunization with nontreated or IFN-γ-primed syngeneic MSC/Neu, the number of circulating neu-specific CD8(+) T cells and titers of anti-neu antibodies were observed to be decreased after immunizations with IFN-γ- plus TNF-α-primed MSC/Neu. In addition, syngeneic MSC/Neu seemed more efficient than IFN-γ-primed MSC/Neu at inducing a protective therapeutic antitumor immune response resulting in the regression of transplanted neu-expressing mammary tumor cells. In vitro antigen-presenting cell assays performed with paraformaldehyde-fixed or live MSC showed that priming with IFN-γ plus TNF-α, compared to priming with IFN-γ alone, increased antigen presentation as well as the production of immunosuppressive factors. These data suggest that whereas MSC could effectively serve as antigen-presenting cells to induce immune responses aimed at tumor autoantigens, these functions are critically regulated by IFN-γ and TNF-α.

  17. Therapeutic approaches for tumor necrosis factor inhibition

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    Maria Letícia de Castro Barbosa

    2011-09-01

    Full Text Available Tumor necrosis factor (TNF consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.O fator de necrose tumoral (do inglês, tumor necrosis factor - TNF consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produ

  18. Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose.

    Science.gov (United States)

    Hao, Lihong; Sheng, Zhenyu; Potian, Joseph; Deak, Adam; Rohowsky-Kochan, Christine; Routh, Vanessa H

    2016-10-01

    A population of Neuropeptide Y (NPY) neurons which co-express Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARC) are inhibited at physiological levels of brain glucose and activated when glucose levels decline (e.g. glucose-inhibited or GI neurons). Fasting enhances the activation of NPY/AgRP-GI neurons by low glucose. In the present study we tested the hypothesis that lipopolysaccharide (LPS) inhibits the enhanced activation of NPY/AgRP-GI neurons by low glucose following a fast. Mice which express green fluorescent protein (GFP) on their NPY promoter were used to identify NPY/AgRP neurons. Fasting for 24h and LPS injection decreased blood glucose levels. As we have found previously, fasting increased c-fos expression in NPY/AgRP neurons and increased the activation of NPY/AgRP-GI neurons by decreased glucose. As we predicted, LPS blunted these effects of fasting at the 24h time point. Moreover, the inflammatory cytokine tumor necrosis factor alpha (TNFα) blocked the activation of NPY/AgRP-GI neurons by decreased glucose. These data suggest that LPS and TNFα may alter glucose and energy homeostasis, in part, due to changes in the glucose sensitivity of NPY/AgRP neurons. Interestingly, our findings also suggest that NPY/AgRP-GI neurons use a distinct mechanism to sense changes in extracellular glucose as compared to our previous studies of GI neurons in the adjacent ventromedial hypothalamic nucleus.

  19. Elevated Dengue Virus Nonstructural Protein 1 Serum Levels and Altered Toll-Like Receptor 4 Expression, Nitric Oxide, and Tumor Necrosis Factor Alpha Production in Dengue Hemorrhagic Fever Patients

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    Denise Maciel Carvalho

    2014-01-01

    Full Text Available Background. During dengue virus (DV infection, monocytes produce tumor necrosis factor alpha (TNF-α and nitric oxide (NO which might be critical to immunopathogenesis. Since intensity of DV replication may determine clinical outcomes, it is important to know the effects of viral nonstructural protein 1 (NS1 on innate immune parameters of infected patients. The present study investigates the relationships between dengue virus nonstructural protein 1 (NS1 serum levels and innate immune response (TLR4 expression and TNF-α/NO production of DV infected patients presenting different clinical outcomes. Methodology/Principal Findings. We evaluated NO, NS1 serum levels (ELISA, TNF-α production by peripheral blood mononuclear cells (PBMCs, and TLR4 expression on CD14+ cells from 37 dengue patients and 20 healthy controls. Early in infection, increased expression of TLR4 in monocytes of patients with dengue fever (DF was detected compared to patients with dengue hemorrhagic fever (DHF. Moreover, PBMCs of DHF patients showed higher NS1 and lower NO serum levels during the acute febrile phase and a reduced response to TLR4 stimulation by LPS (with a reduced TNF-α production when compared to DF patients. Conclusions/Significance. During DV infection in humans, some innate immune parameters change, depending on the NS1 serum levels, and phase and severity of the disease which may contribute to development of different clinical outcomes.

  20. Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology.

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    Brendan N Putko

    Full Text Available BACKGROUND: Various pathways have been implicated in the pathogenesis of heart failure (HF with preserved ejection fraction (HFPEF. Inflammation in response to comorbid conditions, such as hypertension and diabetes, may play a proportionally larger role in HFPEF as compared to HF with reduced ejection fraction (HFREF. METHODS AND RESULTS: This study investigated inflammation mediated by the tumor necrosis factor-alpha (TNFα axis in community-based cohorts of HFPEF patients (n = 100, HFREF patients (n = 100 and healthy controls (n = 50. Enzyme-linked immunosorbent assays were used to investigate levels of TNFα, its two receptors (TNFR1 and TNFR2, and a non-TNFα cytokine, interleukin-6 (IL-6, in plasma derived from peripheral blood samples. Plasma levels of TNFα and TNFR1 were significantly elevated in HFPEF relative to controls, while levels of TNFR2 were significantly higher in HFPEF than both controls and HFREF. TNFα, TNFR1 and TNFR2 were each significantly associated with at least two of the following: age, estimated glomerular filtration rate, hypertension, diabetes, smoking, peripheral vascular disease or history of atrial fibrillation. TNFR2 levels were also significantly associated with increasing grade of diastolic dysfunction and severity of symptoms in HFPEF. CONCLUSIONS: Inflammation mediated through TNFα and its receptors, TNFR1 and TNFR2, may represent an important component of a comorbidity-induced inflammatory response that partially drives the pathophysiology of HFPEF.

  1. Brucella abortus Invasion of Osteocytes Modulates Connexin 43 and Integrin Expression and Induces Osteoclastogenesis via Receptor Activator of NF-κB Ligand and Tumor Necrosis Factor Alpha Secretion.

    Science.gov (United States)

    Pesce Viglietti, Ayelén Ivana; Arriola Benitez, Paula Constanza; Gentilini, María Virginia; Velásquez, Lis Noelia; Fossati, Carlos Alberto; Giambartolomei, Guillermo Hernán; Delpino, María Victoria

    2015-10-12

    Osteoarticular brucellosis is the most common localization of human active disease. Osteocytes are the most abundant cells of bone. They secrete factors that regulate the differentiation of both osteoblasts and osteoclasts during bone remodeling. The aim of this study is to determine if Brucella abortus infection modifies osteocyte function. Our results indicate that B. abortus infection induced matrix metalloproteinase 2 (MMP-2), receptor activator for NF-κB ligand (RANKL), proinflammatory cytokines, and keratinocyte chemoattractant (KC) secretion by osteocytes. In addition, supernatants from B. abortus-infected osteocytes induced bone marrow-derived monocytes (BMM) to undergo osteoclastogenesis. Using neutralizing antibodies against tumor necrosis factor alpha (TNF-α) or osteoprotegerin (OPG), RANKL's decoy receptor, we determined that TNF-α and RANKL are involved in osteoclastogenesis induced by supernatants from B. abortus-infected osteocytes. Connexin 43 (Cx43) and the integrins E11/gp38, integrin-α, integrin-β, and CD44 are involved in cell-cell interactions necessary for osteocyte survival. B. abortus infection inhibited the expression of Cx43 but did not modify the expression of integrins. Yet the expression of both Cx43 and integrins was inhibited by supernatants from B. abortus-infected macrophages. B. abortus infection was not capable of inducing osteocyte apoptosis. However, supernatants from B. abortus-infected macrophages induced osteocyte apoptosis in a dose-dependent manner. Taken together, our results indicate that B. abortus infection could alter osteocyte function, contributing to bone damage.

  2. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

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    Claudia Hernández-Jiménez

    Full Text Available The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5, mechanical ventilation with dry oxygen dispensation, and Group II (n = 5, mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77. This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05. Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02. Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  3. Respiratory mechanics and plasma levels of tumor necrosis factor alpha and interleukin 6 are affected by gas humidification during mechanical ventilation in dogs.

    Science.gov (United States)

    Hernández-Jiménez, Claudia; García-Torrentera, Rogelio; Olmos-Zúñiga, J Raúl; Jasso-Victoria, Rogelio; Gaxiola-Gaxiola, Miguel O; Baltazares-Lipp, Matilde; Gutiérrez-González, Luis H

    2014-01-01

    The use of dry gases during mechanical ventilation has been associated with the risk of serious airway complications. The goal of the present study was to quantify the plasma levels of TNF-alpha and IL-6 and to determine the radiological, hemodynamic, gasometric, and microscopic changes in lung mechanics in dogs subjected to short-term mechanical ventilation with and without humidification of the inhaled gas. The experiment was conducted for 24 hours in 10 dogs divided into two groups: Group I (n = 5), mechanical ventilation with dry oxygen dispensation, and Group II (n = 5), mechanical ventilation with oxygen dispensation using a moisture chamber. Variance analysis was used. No changes in physiological, hemodynamic, or gasometric, and radiographic constants were observed. Plasma TNF-alpha levels increased in group I, reaching a maximum 24 hours after mechanical ventilation was initiated (ANOVA p = 0.77). This increase was correlated to changes in mechanical ventilation. Plasma IL-6 levels decreased at 12 hours and increased again towards the end of the study (ANOVA p>0.05). Both groups exhibited a decrease in lung compliance and functional residual capacity values, but this was more pronounced in group I. Pplat increased in group I (ANOVA p = 0.02). Inhalation of dry gas caused histological lesions in the entire respiratory tract, including pulmonary parenchyma, to a greater extent than humidified gas. Humidification of inspired gases can attenuate damage associated with mechanical ventilation.

  4. Increased tumor necrosis factor-alpha and nitric oxide production by rat macrophages following in vitro stimulation and intravenous administration of the delta-opioid agonist SNC 80.

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    Gomez-Flores, R; Rice, K C; Zhang, X; Weber, R J

    2001-05-04

    Opioids alter immune function by binding to opioid receptors on cells of the immune system, or indirectly by acting on receptors within the central nervous system. Mu-selective opioid agonists are generally associated with immunosuppression, whereas delta-opioid receptor-selective agonists are commonly associated with immunopotentiation. We have previously shown that intracerebroventricular administration of the nonpeptide delta-opioid receptor agonist (+)-4-((alpha R)-alpha-((2S, 5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N, N-diethyl-benzamide (SNC 80) did not alter certain parameters of immunocompetence. In the present study, we studied the in vitro and ex vivo effects of SNC 80 on rat macrophage and lymphocyte functions. We showed that SNC 80 at concentrations of 10(-7) M and 10(-6) M, significantly (P SNC 80 (6.8 mg/kg) significantly (P SNC 80 plus Con A potentiated ex vivo LPS-stimulated macrophage functions. SNC 80 could potentially be utilized in various clinical situations where immunosuppression is undesirable.

  5. Poxvirus host range protein CP77 contains an F-box-like domain that is necessary to suppress NF-kappaB activation by tumor necrosis factor alpha but is independent of its host range function.

    Science.gov (United States)

    Chang, Shu-Jung; Hsiao, Jye-Chian; Sonnberg, Stephanie; Chiang, Cheng-Ting; Yang, Min-Hsiang; Tzou, Der-Lii; Mercer, Andrew A; Chang, Wen

    2009-05-01

    Tumor necrosis factor alpha (TNF-alpha) activates the nuclear factor kappaB (NF-kappaB) signaling pathway that regulates expression of many cellular factors playing important roles in innate immune responses and inflammation in infected hosts. Poxviruses employ many strategies to inhibit NF-kappaB activation in cells. In this report, we describe a poxvirus host range protein, CP77, which blocked NF-kappaB activation by TNF-alpha. Immunofluorescence analyses revealed that nuclear translocation of NF-kappaB subunit p65 protein in TNF-alpha-treated HeLa cells was blocked by CP77. CP77 did so without blocking IkappaBalpha phosphorylation, suggesting that upstream kinase activation was not affected by CP77. Using GST pull-down, we showed that CP77 bound to the NF-kappaB subunit p65 through the N-terminal six-ankyrin-repeat region in vitro. CP77 also bound to Cullin-1 and Skp1 of the SCF complex through a C-terminal 13-amino-acid F-box-like sequence. Both regions of CP77 are required to block NF-kappaB activation. We thus propose a model in which poxvirus CP77 suppresses NF-kappaB activation by two interactions: the C-terminal F-box of CP77 binding to the SCF complex and the N-terminal six ankyrins binding to the NF-kappaB subunit p65. In this way, CP77 attenuates innate immune response signaling in cells. Finally, we expressed CP77 or a CP77 F-box deletion protein from a vaccinia virus host range mutant (VV-hr-GFP) and showed that either protein was able to rescue the host range defect, illustrating that the F-box region, which is important for NF-kappaB modulation and binding to SCF complex, is not required for CP77's host range function. Consistently, knocking down the protein level of NF-kappaB did not relieve the growth restriction of VV-hr-GFP in HeLa cells.

  6. Decreased expression of tumor necrosis factor-alpha-stimulated gene 6 in cumulus cells of the cyclooxygenase-2 and EP2 null mice.

    Science.gov (United States)

    Ochsner, Scott A; Russell, Darryl L; Day, Anthony J; Breyer, Richard M; Richards, Joanne S

    2003-03-01

    Ovulation, the release of fertilizable oocytes from mature follicles, involves tissue remodeling and increased prostaglandin (PG) signaling. Cyclooxygenase (COX)-2 is the rate-limiting enzyme during PG synthesis. Female mice null for either COX-2 or the PGE(2) receptor EP2 are infertile, show decreased ovulation, and exhibit abnormal cumulus expansion. Cumulus expansion is the production of a complex extracellular matrix surrounding the cumulus-oocyte complex (COC). Matrix components consist of hyaluronan, proteoglycans, and proteins with hyaluronan binding domains. One such hyaluronan binding protein is TNFalpha-stimulated gene 6 (TSG-6). By various methods, we show induction of TSG-6 and hyaluronan synthase-2 mRNA in ovaries of mice treated with pregnant mare serum gonadotropin and human chorionic gonadotropin. By in situ hybridization, we show that both genes are expressed in periantral mural granulosa cells and cumulus cells of the mouse ovary. Notably, RT-PCR and in situ hybridization show that TSG-6 mRNA but not hyaluronan synthase-2 mRNA expression is selectively reduced in cumulus cells of COX-2 and EP2 null mice. Western analysis further confirms that TSG-6 protein is reduced in isolated COCs but remains covalently associated with inter alpha-trypsin inhibitor in COX-2 null mice. These observations identify TSG-6 as a target of PG action and show that its production in ovulatory follicles is associated with proper formation of the cumulus-derived extracellular matrix.

  7. Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

    DEFF Research Database (Denmark)

    Madsen, Pernille M; Clausen, Bettina H; Degn, Matilda;

    2016-01-01

    Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor...

  8. Inhibition of tumor necrosis factor-alpha and cyclooxigenase-2 by Isatin: a molecular mechanism of protection against TNBS-induced colitis in rats.

    Science.gov (United States)

    Socca, Eduardo Augusto Rabelo; Luiz-Ferreira, Anderson; de Faria, Felipe Meira; de Almeida, Ana Cristina; Dunder, Ricardo José; Manzo, Luis Paulo; Brito, Alba Regina Monteiro Souza

    2014-02-25

    Isatin, an indole alkaloid has been shown to have anti-microbial, anti-tumor and anti-inflammatory effects. Due to its findings, we evaluated whether this alkaloid would have any effect on TNBS-induced colitis. Animals (male Unib:WH rats, aged 8 weeks old) were induced colitis through a rectal administration of 2,4,6-trinitrobenzene sulphonic acid using a catheter inserted 8 cm into the rectum of the animals. The rats were divided into two major groups: non-colitic and colitic. The colitic group was sub-divided into 6 groups (10 animals per group): colitic non-treated, Isatin 3; 6; 12.5; 18.75 and 25 mg/kg. Our main results showed that the oral treatment with Isatin 6 and 25 mg/kg were capable of avoiding the increase in TNF-α, COX-2 and PGE₂ levels when compared to the colitic non-treated group. Interestingly, the same doses (6 and 25 mg/kg) were also capable of preventing the decrease in IL-10 levels comparing with the colitic non-treated group. The levels of MPO, (an indirect indicator of neutrophil presence), were also maintained lower than those of the colitic non-treated group. Isatin also prevented the decrease of SOD activity and increase of GSH-Px and GSH-Rd activity as well as the depletion of GSH levels. In conclusion, both pre-treatments (6 and 25 mg/kg) were capable of protecting the gut mucosa against the injury caused by TNBS, through the combination of antioxidant and anti-inflammatory properties, which, together, showed a protective activity of the indole alkaloid Isatin.

  9. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

    DEFF Research Database (Denmark)

    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected...... by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  10. Tumor necrosis factor interaction with gold nanoparticles

    Science.gov (United States)

    Tsai, De-Hao; Elzey, Sherrie; Delrio, Frank W.; Keene, Athena M.; Tyner, Katherine M.; Clogston, Jeffrey D.; Maccuspie, Robert I.; Guha, Suvajyoti; Zachariah, Michael R.; Hackley, Vincent A.

    2012-05-01

    We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis, attenuated total reflectance-Fourier transform infrared spectroscopy, fluorescence assay, and enzyme-linked immunosorbent assay. The native TNF used in this study exists in the active homotrimer configuration prior to conjugation. After binding to AuNPs, the maximum surface density of TNF is (0.09 +/- 0.02) nm-2 with a binding constant of 3 × 106 (mol L-1)-1. Dodecyl sulfate ions induce desorption of monomeric TNF from the AuNP surface, indicating a relatively weak intermolecular binding within the AuNP-bound TNF trimers. Anti-TNF binds to both TNF-conjugated and citrate-stabilized AuNPs, showing that non-specific binding is significant. Based on the number of anti-TNF molecules adsorbed, a substantially higher binding affinity was observed for the TNF-conjugated surface. The inclusion of thiolated polyethylene glycol (SH-PEG) on the AuNPs inhibits the binding of anti-TNF, and the amount of inhibition is related to the number ratio of surface bound SH-PEG to TNF and the way in which the ligands are introduced. This study highlights the challenges in quantitatively characterizing complex hybrid nanoscale conjugates, and provides insight on TNF-AuNP formation and activity.We report on a systematic investigation of molecular conjugation of tumor necrosis factor-α (TNF) protein onto gold nanoparticles (AuNPs) and the subsequent binding behavior to its antibody (anti-TNF). We employ a combination of physical and spectroscopic characterization methods, including electrospray-differential mobility analysis, dynamic light scattering, polyacrylamide gel electrophoresis

  11. Tumor necrosis factor alpha promotes the proliferation of human nucleus pulposus cells via nuclear factor-κB, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase.

    Science.gov (United States)

    Wang, Xiao-Hu; Hong, Xin; Zhu, Lei; Wang, Yun-Tao; Bao, Jun-Ping; Liu, Lei; Wang, Feng; Wu, Xiao-Tao

    2015-04-01

    Although tumor necrosis factor alpha (TNF-α) is known to play a critical role in intervertebral disc (IVD) degeneration, the effect of TNF-α on nucleus pulposus (NP) cells has not yet been elucidated. The aim of this study was to explore the effect of TNF-α on proliferation of human NP cells. NP cells were treated with different concentrations of TNF-α. Cell proliferation was determined by cell counting kit-8 (CCK-8) analysis and Ki67 immunofluorescence staining, and expression of cyclin B1 was studied by quantitative real-time RT-PCR. Cell cycle was measured by flow cytometry and cell apoptosis was analyzed using an Annexin V-fluorescein isothiocyanate (FITC) & propidium iodide (PI) apoptosis detection kit. To identify the mechanism by which TNF-α induced proliferation of NP cells, selective inhibitors of major signaling pathways were used and Western blotting was carried out. Treatment with TNF-α increased cell viability (as determined by CCK-8 analysis) and expression of cyclin B1 and the number of Ki67-positive and S-phase NP cells, indicating enhancement of proliferation. Consistent with this, NP cell apoptosis was suppressed by TNF-α treatment. Moreover, inhibition of NF-κB, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) blocked TNF-α-stimulated proliferation of NP cells. In conclusion, the current findings suggest that the effect of TNF-α on IVD degeneration involves promotion of the proliferation of human NP cells via the NF-κB, JNK, and p38 MAPK pathways.

  12. Expression of tumor necrosis factor-alpha converting enzyme and matrix metalloproteinase-3 in proliferated synovium in a patient with synovitis-acne-pustulosis-hyperostosis-osteitis syndrome: a case report

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    Komiya Koichiro

    2009-09-01

    Full Text Available Abstract Introduction Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO syndrome is a rare disorder. The etiology remains unknown and the treatment is still empirical. Synovitis is one of the major manifestations, but information on histopathological features is still lacking. In this case, we investigated the histopathological features of SAPHO syndrome synovitis. Case presentation We present the case of a 53-year-old Japanese woman with SAPHO syndrome accompanied by marked knee synovitis and palmoplantar pustulosis. We found abundant sterile joint fluid in the right knee, and a blood test showed abnormally high values of C-reactive protein (17.26 mg/dl and matrix metalloproteinase-3 (800 ng/ml. Arthroscopic surgery revealed marked proliferation of villous synovial tissues similar to rheumatoid arthritis and standard microscopic findings were also similar to rheumatoid arthritis. Furthermore, for the first time, we demonstrated by immunohistochemistry the expression of tumor necrosis factor-alpha (TNF-α converting enzyme, TNF-α and matrix metalloproteinase-3 in the proliferated synovial lining cells. After arthroscopic synovectomy, her knee symptoms immediately diminished and laboratory data (matrix metalloproteinase-3 and C-reactive protein normalized within 2 weeks of surgery. Conclusion We demonstrate the expression of TNF-α converting enzyme, TNF-α and matrix metalloproteinase-3 in SAPHO syndrome synovitis for the first time and also show, both macro- and microscopically, the similarity between SAPHO syndrome and rheumatoid arthritis synovitis. These new findings support the recently reported successful treatment of SAPHO syndrome with antirheumatic drugs, especially with anti-TNF-α agents.

  13. The role of tumor necrosis factor-alpha -308 G/A and transforming growth factor-beta 1 -915 G/C polymorphisms in childhood idiopathic thrombocytopenic purpura

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    Emel Okulu

    2011-09-01

    Full Text Available Objective: To increase our understanding of the etiology of idiopathic thrombocytopenic purpura (ITP some cytokine gene polymorphisms were analyzed for susceptibility to the disease. The aim of this study was to investigate the role of tumor necrosis factor-alpha (TNF-α -308 G/A and transforming growth factor-beta 1 (TGF-β1 –915 G/C polymorphisms in the development and clinical progression of childhood ITP.Materials and Methods: In all, 50 pediatric patients with ITP (25 with acute ITP and 25 with chronic ITP and 48 healthy controls were investigated via LightCycler® PCR analysis for TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms.Results: The frequency of TNF-α -308 G/A polymorphism was 20%, 16%, and 22.9% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The frequency of TGF-β1 -915 G/C polymorphism was 16%, 8%, and 8.3% in the acute ITP patients, chronic ITP patients, and controls, respectively (p>0.05. The risk of developing ITP and clinical progression were not associated with TNF-α -308 G/A (OR: 0.738, 95% CI: 0.275-1.981, and OR: 0.762, 95% CI: 0.179-3.249 or TGF-β1 -915 G/C (OR: 1.5, 95% CI: 0.396-5.685, and OR: 0.457, 95% CI: 0.076-2.755 polymorphisms. Conclusion: The frequency of TNF-α -308 G/A and TGF-β1 -915 G/C polymorphisms did not differ between pediatric ITP patients and healthy controls, and these polymorphisms were not associated with susceptibility to the development and clinical progression of the disease.

  14. Plasmids expressing interleukin-10 short hairpin RNA mediate IL-10 knockdown and enhance tumor necrosis factor alpha and interferon gamma expressions in response to porcine reproductive and respiratory syndrome virus.

    Science.gov (United States)

    Charerntantanakul, Wasin; Kasinrerk, Watchara

    2012-04-15

    Porcine reproductive and respiratory syndrome virus (PRRSV) has been suggested to exploit interleukin-10 (IL-10) to suppress immune defense of infected pigs. The present study constructed plasmids encoding selected short hairpin RNA specific to porcine IL-10 mRNA (pIL-10sh) to knockdown IL-10 transcription and investigated the suppressive effect of PRRSV-induced IL-10 on various immune marker expressions. Naïve blood monocytes from eight PRRSV-seronegative pigs were transfected with pIL-10sh and pNeg (plasmid vector) prior to PRRSV inoculation and subsequent lipopolysaccharide (LPS) stimulation. The mRNA expressions of IL-10, IL-1β, IL-12p40, tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), transforming growth factor beta (TGFβ), CD80, and CD86 were evaluated by real-time PCR. The IL-10, TNFα, and IFNγ protein productions were determined by ELISA. Compared with non-transfected monocyte control, transfection with selected pIL-10sh (pIL-10sh1), but not other pIL-10sh nor pNeg, significantly reduced IL-10 expression and significantly enhanced TNFα and IFNγ expressions. Slight increases in IL-1β, IL-12p40, CD80, and CD86 expressions were also observed. Neither pIL-10sh1 nor pNeg transfection affected TGFβ expression. Our results indicate that PRRSV does exploit IL-10 to suppress the expressions of pro-inflammatory cytokines, mainly TNFα and IFNγ, and co-stimulatory molecules, CD80 and CD86.

  15. Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma

    NARCIS (Netherlands)

    T.E. Lans; T.L.M. ten Hagen (Timo); R. van Horssen (Remco); P.C. Wu; S.T. van Tiel (Sandra); S.K. Libutti; H.R. Alexander; A.M.M. Eggermont (Alexander)

    2002-01-01

    textabstractBACKGROUND: Experiments with tumor necrosis factor alpha (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the

  16. Association analysis of tumor necrosis factor alpha promoter polymorphisms with schizophrenia%肿瘤坏死因子-α基因-308G/A多态性与精神分裂症的关联研究

    Institute of Scientific and Technical Information of China (English)

    戴俊平; 赵振环; 蔡广惠; 黄金满

    2008-01-01

    Objective To explore relationship of G308A polymorphism in the tumor necrosis factor a (TNF-α) gene and TNF-α serum level with schizophrenia. Methods The G308A polymorphism in TNFa was tested by PCR-based RFLP in 155 schizophrenic family trios from Guangdong Province by polymerase chain reaction and restriction fragment length polymorphism techniques, and level of TNF-alpha in serum by ELISA. Results Haplotype relative risk revealed that the transmitted A allelic frequency in patients was significantly higher than that in their parents (27.1% vs 15.0%, P< 0.01), and serum level of TNF-alpha in patients was also higher than that in their parents [(197.3±83.4) pg/ml vs (95.2±46.8) pg/ml, P<0.05)]. Conclusions There is rela-tionship of the TNF-α promoter polymorphism at position -308 and TNF-α serum level with schizophrenia,indica- ting that it is the candidate gene of schizophrenia.%目的 了解肿瘤坏死因子-α(TNF-α)基因-308G/A多态性、血清水平与广东地区精神分裂症的相关性.方法 用聚合酶链反应一限制性片段长度多态性技术检测155个核心家系精神分裂症患者及其父母外周血的TNF-α基因启动子区域-308G/A位点基因多态性;采用酶联免疫吸附法测定血清TNF-α水平.结果 TNF-α基因-308位点变异的G/A基因型频率在精神分裂症组中比父母对照组明显升高(27.1%;15.0%,P<0.01),血清TNF-α水平也显著高于对照组[(197.3±83.4)pg/ml;(95.2±46.8)pg/ml,P<0.05)].结论 TNF-α基因-308位点G/A多态性和血清TNF-α水平增高与精神分裂症发生相关联,支持TNF-α基因是精神分裂症的候选基因.

  17. A matrix of cholesterol crystals, but not cholesterol alone, primes human monocytes/macrophages for excessive endotoxin-induced production of tumor necrosis factor-alpha. Role in atherosclerotic inflammation?

    DEFF Research Database (Denmark)

    Bendtzen, Klaus; Christensen, Ole; Nielsen, Claus Henrik

    2014-01-01

    When exposed to small amounts of bacterial endotoxin, matrices of cholesterol crystals, but not cholesterol itself, primed human monocytes/macrophages to a highly augmented (>10-fold) production of inflammatory tumor necrosis factor-α. Priming also sensitized the cells, as 10- to 100-fold lower...... suggest that cholesterol matrix formation may play a pathogenic role in atherosclerotic inflammation, and they indicate a mechanism by which bacteria and/or bacterial products may play a role in processes leading to arteriosclerosis....

  18. Iron-independent induction of ferritin H chain by tumor necrosis factor.

    OpenAIRE

    Miller, L L; Miller, S C; Torti, S. V.; Tsuji, Y; Torti, F M

    1991-01-01

    Iron increases the synthesis of the iron-storage protein, ferritin, largely by promoting translation of preexisting mRNAs for both the H and L ferritin isoforms (H, heavy, heart, acidic; L, light, liver, basic). We have recently cloned and sequenced a full-length cDNA to murine ferritin H and identified ferritin H as a gene induced by tumor necrosis factor alpha (TNF-alpha, cachectin). Using primary human myoblasts, we have now examined the relationship between TNF-alpha and iron in regulatin...

  19. Cytokine gene polymorphism [tumor necrosis factor-alpha (-308), IL-10 (-1082), IL-6 (-174), IL-17F, 1RaVNTR] in pediatric patients with primary immune thrombocytopenia and response to different treatment modalities.

    Science.gov (United States)

    Mokhtar, Galila M; El-Beblawy, Nagham M S; Adly, Amira A; Elbarbary, Nancy S; Kamal, Tarek M; Hasan, Esraa M

    2016-04-01

    To evaluate the association between development, progression, and response to therapy among patients with immune thrombocytopenia (ITP) and different cytokine gene polymorphisms known to be related to autoimmunity [tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6, IL-17, IL-1Ra]. A total of 50 pediatric patients with ITP (20 newly diagnosed, 30 chronic) and 50 healthy controls were investigated via PCR-restriction fragment length polymorphism analysis for cytokine gene polymorphism. Compared with controls, all patients showed a higher frequency of IL-6-174 CC [P = 0.0001, odds ratio (OR) = 7.048, 95% confidence interval (CI) = 2.18-22.7], higher GA genotype of TNF-α (-308) (P = 0.001, OR = 6.469, 95% CI = 2.0-20.9), higher CC genotype of IL-17F (P = 0.0001, OR = 55.545, 95% CI = 14.4-213.2), higher GG of IL-10-1082 (P = 0.029, OR = 3.6, 95% CI = 1.08-12.18), and A1A2 genotype of IL-1Ra (P = 0.039, OR = 2.374, 95% CI = 1.03-5.4). IL-10 GA and IL-1Ra A1A1 genotypes were higher among chronic patients (P = 0.042, P = 0.001 respectively) compared with newly diagnosed ones. Best platelet response to steroid treatment was found among GC genotype of IL-6 (-174) and GG genotype of IL-10 (-1082) in all patients with ITP. This suggests that previously mentioned cytokine gene polymorphisms possibly contribute to the susceptibility of acquisition of childhood ITP. Furthermore, GA genotype of IL-10 and A1A1 genotype of IL-1Ra polymorphisms are associated with increased risk of chronic ITP. IL-6 (-174) and IL-10 (-1082) genes might play a role in the effectiveness of steroid therapy among patients with ITP.

  20. Effects of tumor necrosis factor-alpha on calcium movement in rat ventricular myocytes%肿瘤坏死因子α对大鼠心室肌细胞钙转运的影响

    Institute of Scientific and Technical Information of China (English)

    李小强; 招明高; 梅其柄; 张延凤; 曹蔚; 王海芳; 陈丹; 崔毅

    2003-01-01

    AIM: To study the effects of tumor necrosis factor-alpha (TNF-α) on calcium movement in rat ventricular myocytes. METHODS: Intracellular free Ca2+ concentration was measured with calcium fluorescent probe Fluo-3/AM and laser confocal microscope. L-type calcium current (Ica,L) was recorded with the whole-cell configuration of the patch-clamp techniques. RESULTS: At 2, 20 and 200 μg/L, TNF-α was found to increase intracellular free Ca2+ concentration in a dose-dependent manner illustrated by the increment of calcium fluorescence density with laser confocal microscope. Nicardipine 0.5 μmol/L slightly attenuated TNF-α-induced response. When the cardiac myocytes were exposed to caffeine (100 mmol/L) for 30 min, TNF-α failed to induce any change of intracellular free calcium. However, it was found that TNF-α inhibited Ica,L in whole-cell patch-clamp experiments. At 2, 20, and 200 μg/L, TNF-α decreased peak Ica,L by 3.9 % (-5.1 pA/pF+0.3 pA/pF vs -4.9 pA/pF+0.2 pA/pF, n=9, P>0.05), 15.7 % (-5.1 pA/pF+0.3 pA/pF vs -4.3 pA/pF+0.3 pA/pF, n=9, P<0.05) and 19.6 % (-5.1 pA/pF+0.3 pA/ pF vs -4.1 pA/pF+0.4 pA/pF, n=9, P<0.01), respectively. It shifted the steady-state inactivation curve of Ica,L to the left (V1/2 shifted from -28.7 mV+0.3 mV to -37.8 mV+1.4 mV, n=7, P<0.05), while it took no effects on steadystate activation and recovery from inactivation. CONCLUSION: TNF-α inhibited Ica,L in rat ventricular myocytes,while increasing the intercellular free Ca2+ level due to the release of Ca2+ from intracellular stores.

  1. miR-29a suppresses MCF-7 cell growth by downregulating tumor necrosis factor receptor 1.

    Science.gov (United States)

    Zhao, Yiling; Yang, Fenghua; Li, Wenyuan; Xu, Chunyan; Li, Li; Chen, Lifei; Liu, Yancui; Sun, Ping

    2017-02-01

    Tumor necrosis factor receptor 1 is the main receptor mediating many tumor necrosis factor-alpha-induced cellular events. Some studies have shown that tumor necrosis factor receptor 1 promotes tumorigenesis by activating nuclear factor-kappa B signaling pathway, while other studies have confirmed that tumor necrosis factor receptor 1 plays an inhibitory role in tumors growth by inducing apoptosis in breast cancer. Therefore, the function of tumor necrosis factor receptor 1 in breast cancer requires clarification. In this study, we first found that tumor necrosis factor receptor 1 was significantly increased in human breast cancer tissues and cell lines, and knockdown of tumor necrosis factor receptor 1 by small interfering RNA inhibited cell proliferation by arresting the cell cycle and inducing apoptosis. In addition, miR-29a was predicted as a regulator of tumor necrosis factor receptor 1 by TargetScan and was shown to be inversely correlated with tumor necrosis factor receptor 1 expression in human breast cancer tissues and cell lines. Luciferase reporter assay further confirmed that miR-29a negatively regulated tumor necrosis factor receptor 1 expression by binding to the 3' untranslated region. In our functional study, miR-29a overexpression remarkably suppressed cell proliferation and colony formation, arrested the cell cycle, and induced apoptosis in MCF-7 cell. Furthermore, in combination with tumor necrosis factor receptor 1 transfection, miR-29a significantly reversed the oncogenic role caused by tumor necrosis factor receptor 1 in MCF-7 cell. In addition, we demonstrated that miR-29a suppressed MCF-7 cell growth by inactivating the nuclear factor-kappa B signaling pathway and by decreasing cyclinD1 and Bcl-2/Bax protein levels. Taken together, our results suggest that miR-29a is an important regulator of tumor necrosis factor receptor 1 expression in breast cancer and functions as a tumor suppressor by targeting tumor necrosis factor receptor 1 to

  2. The role of tumour necrosis factor alpha and soluble tumour necrosis factor alpha receptors in the symptomatology of schizophrenia.

    Science.gov (United States)

    Turhan, Levent; Batmaz, Sedat; Kocbiyik, Sibel; Soygur, Arif Haldun

    2016-07-01

    Background Immunological mechanisms may be responsible for the development and maintenance of schizophrenia symptoms. Aim The aim of this study is to measure tumour necrosis factor-alpha (TNF-α), soluble tumour necrosis factor-alpha receptor I (sTNF-αRI), and soluble tumour necrosis factor-alpha receptor II (sTNF-αRII) levels in patients with schizophrenia and healthy individuals, and to determine their relationship with the symptoms of schizophrenia. Methods Serum TNF-α, sTNF-αRI and sTNF-αRII levels were measured. The Positive and Negative Syndrome Scale (PANSS) was administered for patients with schizophrenia (n = 35), and the results were compared with healthy controls (n = 30). Hierarchical regression analyses were undertaken to predict the levels of TNF-α, sTNF-αRI and sTNF-αRII. Results No significant difference was observed in TNF-α levels, but sTNF-αRI and sTNF-αRII levels were lower in patients with schizophrenia. Serum sTNF-αRI and sTNF-αRII levels were found to be negatively correlated with the negative subscale score of the PANSS, and sTNF-αRI levels were also negatively correlated with the total score of the PANSS. Smoking, gender, body mass index were not correlated with TNF-α and sTNF-α receptor levels. Conclusions These results suggest that there may be a change in anti-inflammatory response in patients with schizophrenia due to sTNF-αRI and sTNF-αRII levels. The study also supports low levels of TNF activity in schizophrenia patients with negative symptoms.

  3. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

    OpenAIRE

    2007-01-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune...

  4. The interferon-gamma-induced GTPase, mGBP-2, inhibits tumor necrosis factor alpha (TNF-alpha) induction of matrix metalloproteinase-9 (MMP-9) by inhibiting NF-kappaB and Rac protein.

    Science.gov (United States)

    Balasubramanian, Sujata; Fan, Meiyun; Messmer-Blust, Angela F; Yang, Chuan H; Trendel, Jill A; Jeyaratnam, Jonathan A; Pfeffer, Lawrence M; Vestal, Deborah J

    2011-06-03

    Matrix metalloproteinase-9 (MMP-9) is important in numerous normal and pathological processes, including the angiogenic switch during tumor development and tumor metastasis. Whereas TNF-α and other cytokines up-regulate MMP-9 expression, interferons (IFNs) inhibit MMP-9 expression. We found that IFN-γ treatment or forced expression of the IFN-induced GTPase, mGBP-2, inhibit TNF-α-induced MMP-9 expression in NIH 3T3 fibroblasts, by inhibiting MMP-9 transcription. The NF-κB transcription factor is required for full induction of MMP-9 by TNF-α. Both IFN-γ and mGBP-2 inhibit the transcription of a NF-κB-dependent reporter construct, suggesting that mGBP-2 inhibits MMP-9 induction via inhibition of NF-κB-mediated transcription. Interestingly, mGBP-2 does not inhibit TNF-α-induced degradation of IκBα or p65/RelA translocation into the nucleus. However, mGBP-2 inhibits p65 binding to a κB oligonucleotide probe in gel shift assays and to the MMP-9 promoter in chromatin immunoprecipitation assays. In addition, TNF-α activation of NF-κB in NIH 3T3 cells is dependent on Rac activation, as evidenced by the inhibition of TNF-α induction of NF-κB-mediated transcription by a dominant inhibitory form of Rac1. A role for Rac in the inhibitory action of mGBP-2 on NF-κB is further shown by the findings that mGBP-2 inhibits TNF-α activation of endogenous Rac and constitutively activate Rac can restore NF-κB transcription in the presence of mGBP-2. This is a novel mechanism by which IFNs can inhibit the cytokine induction of MMP-9 expression.

  5. 肿瘤坏死因子-α拮抗剂引发结核二例分析并文献复习%Tuberculosis following tumor necrosis factor alpha antagonists therapy: two cases report and fiteratnere review

    Institute of Scientific and Technical Information of China (English)

    梁东风; 张江林; 黄烽

    2008-01-01

    Objective To improve clinicians' understanding of tuberculosis as the adverse event of the tumor necrosis factor alpha (TNF-α) antagonists therapy. Methods Two rheumatoid arthritis (RA) patients were reported to develop lymphoid tuberculosis and pulmonary tuberculoma after TNF-α antagonists therapy. The relevant literature were reviewed. Results The first ease was a 62 year-old female RA patient. Her skin PPD reaction was negative and chest X-ray was normal before the therapy. Following 4 doses of infliximab injection (each dose of 3 mg/kg) which were completed within 3 months, the patient developed fight supraclavicular lymphoids tuberculosis in the 5th month after the last treatment. The patient completely recovered after lymphoids excision and antituberculosis therapy with 4 anti-tuberculosis medications combination. The second case was a 44 year-old female RA patient. She did not take the skin PPD test and chest X-ray before the therapy. The patient developed fever and chest distress after etanercept therapy (25 mg hypodermic twice per week ) for 1.5 months. The chest X-ray showed a shadow in the median lobe of the right lung, which had gradually developed to a pulmonary tuberculoma. The patient's physical condition improved after the tubereuloma resection. It has been reported in recent years that ① TNF-α antagonists therapy could increase the incidence of tuberculosis, ② the incidence at which infliximab associated tuberculosis was higher than etanercept, ③ the majority of the patient having tuberculosis were old people, and ④ the incidence of extrapulmonary tuberculosis and the disseminated tuberculosis were higher than regular tuberculosis. Conclusion TNF-α antagonists may decrease the host defense ability against mycobacterium tuberculosis and increase the incidence of tuberculosis. The pre-treatment tuberculosis screening, as well as tuberculosis monitoring during and after treatment is mandatory.%目的 提高临床医生对肿瘤坏死因

  6. Allelic frequency of G380A polymorphism of tumor necrosis factor alpha gene and relation with cardiovascular risk factors and adipocytokines in obese patients Frecuencia alélica del polimorfismo G380A del factor de necrosis tumoral alpha y relación con factores de riesgo cardiovascular y adipocitoquinas en pacientes obesos

    Directory of Open Access Journals (Sweden)

    D. A. De Luis

    2011-08-01

    Full Text Available Background: The aim of our study was to investigate the allelic frequency of the G308A polymorphism in the TNF alpha gene and the influence of G308A this polymorphism on cardiovascular risk factors and adipokine levels in obese patients. Design: A population of 834 obesity patients was analyzed. A nutritional evaluation and a blood analysis were performed. The statistical analysis was performed for the combined G308A and A308A as mutant group and type G308G as wild group. Results: A total of 630 patients (181 males/449 females (75.5% had the genotype G308/G308 (wild genotype group with an average age of 43.5 ± 14.8 years, 188 patients (61 males/127 females (22.5% had the genotype G308/A308 (mutant genotype group-heterozygote and 16 patients (5 males/11 females (1.9% with an average age of 44.5 ± 14.2 years had the genotype A308/A308 (mutant group-homorozygote with an average age of 44.3 ± 11.4 years, without statistical differences in the mean age or sex distribution. Genotypes G308/A308 and A308/A308 was designed (mutant genotype group as a dominant model. Allelic frequency of the A substitucion -308 was 13.19%. Anthropometric, adipokines, insulin resistance, lipid levels ad dietary intake were similar in both genotypes. Conclusion: In conclusion, allelic frequency of G308A polymorphism is is in accordance with allelic frequencies observed in other populations. Carries of A308 allele have the same anthropometric and metabolic profile than wild type carriers.Antecedentes: El objetivo de nuestro estudio fue investigar la frecuencia alélica del polimorfismo G308A del gen TNF alfa y su influencia en los factores de riesgo cardiovascular y los niveles de adipocinas en pacientes obesos. Diseño: Se estudió una población de 834 pacientes obesos. Se realizaron una evaluación nutricional y un análisis de sangre. El análisis estadístico se realizó para el genotipo combinado G308A y A308A como grupo de mutantes y G308G tipo de grupo salvaje

  7. 肿瘤坏死因子TNF-α基因多态性与精神分裂症易感性关系的Meta分析%Meta analysis on the association of polymorphisms of tumor necrosis factor-alpha gene with schizophrenia risk

    Institute of Scientific and Technical Information of China (English)

    刘军; 虞洪; 顾宝罗; 贺超奇

    2011-01-01

    Objective An increasing amount of evidence suggests that the schizophrenia is associated with the polymorphisms of tumor necrosis factor-alpha (TNF-α) gene. However, the results of different studies are often inconsistent. So, to investigate the association of TNF-α polymorphisms (-308,-238,-857 and -1031 ) with schizophrenia risk by Meta analysis. Methods Studies and thesises published from 1989 to 2010 were searched through PubMed by the keywords: schizophrenia, TNF a, tumor necrosis factor a, tumor necrosis factor alpha and TNF alpha,and through CNKI by the keywords 多态性( polymorphism), 肿瘤坏死因子( tumor necrosis factor-alpha) and 精神分 裂症(schizophrenia). The results were expressed as odds ratios (OR) and their 95% confidence intervals (CI).Results 13 studies were found. The results by Meta analysis suggested no significant association between -308 polymorphism and schizophrenia risk ( G/A allele: pooled OR = 1.06, 95% CI = 0. 79-1.42, P = 0.71 ). No significant difference in genotype distribution of -308 polymorphism in schizophrenia was found. Subgroup analysis also showed that there was no correlation between the populations of Caucasian and Asian. For the -238,-857 and -1031 polymorphisms,Meta analysis showed no correlation with schizophrenia risk. Conclusions There is no significant correlation between TNF-α polymorphisms (-308, -238, -857 and -1031 ) and schizophrenia risk.%目的 有越来越多的证据表明精神分裂症和肿瘤坏死因子α(TNF-α)基因的多态性存在关联,但是许多研究的结果常常是相互矛盾的,因此,我们通过Meta分析的方法来评价TNF-α位点(-308、-238、-857和-1031)多态性和精神分裂症易感性之间的关系.方法 检索PubMed和中国学术期刊网数据库,使用的关键词包括schizophrenia、TNF a、tumor necrosis factor a、tumor necrosis factor alpha、TNF alpha、多态性、肿瘤坏死因子和精神分裂症.检索时间为1989至2010年公开发表

  8. Intravenous immunoglobulin reduces serum tumor necrosis factor a in patients with Guillain-Barre Syndrome

    Directory of Open Access Journals (Sweden)

    Reuben S

    2003-10-01

    Full Text Available Background: Tumor necrosis factor a TNF-alpha has a possible role in the pathogenesis of the Guillain-Barre' syndrome (GBS. Aims: To study the effect of intravenous immunoglobulin (IVIg on serum TNF-alpha concentrations in patients with GBS. Material and Methods: The effect of IVIg on TNF-alpha was evaluated in 36 patients with GBS. Serum TNF-alpha concentration was measured by enzyme-linked immunosorbent assay (ELISA. The sera of 22 (61% patients with GBS showed elevated concentrations of TNF-alpha (35-182 pg/ml and these sera were individually incubated in vitro with IVIg (0.25mg/ml at 37°C for 24 hours. Results: The serum TNF-alpha concentrations in the 22 GBS patients with elevated levels showed a steady decline (60.34—19.78 pg/ml following incubation with IVIg. These 22 patients also received IVIg therapy, and serum TNF-alpha concentrations showed a significant decline (65.5—9.75 pg/ml at the end of the therapy. At the time of discharge from the hospital, there was a positive correlation between neurological recovery and decline in TNF-alpha concentrations in these 22 GBS patients. Conclusions: The results of this study indicate that elevated levels of TNF-alpha occur in a proportion of patients with GBS and in these patients elevated serum TNF-alpha levels decline with IVIg therapy.

  9. Retraction RETRACTION of "Tumor necrosis factor alpha gene -308G>A polymorphism association with the risk of esophageal cancer in a Han Chinese population" by H. Zhao, H.W. Zhang, T. Zhang and X.M. Gu - Genet. Mol. Res. 15 (2): gmr.15025866 DOI: http://dx.doi.org/10.4238/gmr.15025866.

    Science.gov (United States)

    Zhao, H; Zhang, H W; Zhang, T; Gu, X M

    2016-10-07

    The retracted article is: Zhao H, Zhang HW, Zhang T and Gu XM (2016). Tumor necrosis factor alpha gene -308G>A polymorphism association with the risk of esophageal cancer in a Han Chinese population. Genet. Mol. Res. 15: gmr.15025866. Two major concerns were found in this article. Firstly, it was found to be substantially equal to the article "Tumor necrosis factor-alpha gene -308G > A polymorphism alters the risk of hepatocellular carcinoma in a Han Chinese population" published in the Diagnostic Pathology Diagnostic Pathology (2014) 9: 199, by Feng et al.; licensee BioMed Central. 2014 - DOI: 10.1186/s13000-014-0199-3. Secondly, the authors do not discuss limitations of their approaches in the discussion. The discussion is largely an elaboration of the literature in the introduction part. However, even in that context, the discussion does not appropriately review the literature and there are frequent references to conclusions that are not supported by the cited literature. The GMR editorial staff was alerted and after a thorough investigation, there is strong reason to believe that the peer review process was failure. Also, after review and contacting the authors, the editors of Genetics and Molecular Research decided to retract this article in accordance with the recommendations of the Committee on Publication Ethics (COPE). The authors and their institutions were advised of this serious breach of ethics.

  10. O papel do Fator de Necrose Tumoral Alfa (TNF-alfa no processo de erosão óssea presente no colesteatoma adquirido da orelha média The role of Tumor Necrosis Factor -Alpha (TNF- alpha in bone resorption present in middle ear cholesteatoma

    Directory of Open Access Journals (Sweden)

    Rodrigo Faller Vitale

    2007-02-01

    Full Text Available O colesteatoma adquirido da orelha média causa erosão óssea, com altas taxas de morbidade e mortalidade. O TNF-alfa (TNF-alfa lambda uma das principais citocinas envolvidas neste processo. OBJETIVO: Avaliar o papel do TNF-alfa na reabsorsão óssea e a ação dele no colesteatoma. MATERIAL E MÉTODOS: Foi realizado um levantamento e uma revisão crítica da literatura. RESULTADOS: Todos os autores estudados concordam com a importância do TNF-alfa no processo de reabsorção óssea presente no colesteatoma e com o grau de destruição observado. Diferentes trabalhos demonstraram que o TNF-alfa é capaz de provocar erosão óssea, através de diferentes vias de ação. Ele pode estimular a diferenciação e a maturação dos osteoclastos ou, ainda, agir na matriz óssea expondo-a à ação dos osteoclastos. Existe a possibilidade de inibir a ação do TNF-alfa, diminuindo seus efeitos e prevenindo a perda óssea em doenças como a artrite reumatóide. Não existe, entretanto, trabalhos específicos em colesteatoma. Não existe consenso sobre a sua localização. Estas diferenças, provavelmente, ocorrem devido à distribuição dos receptores. CONCLUSÃO: O TNF-alfa, presente no colesteatoma promove a reabsorsão óssea, juntamente com outras citocinas (RANKL e IL-1, estando relacionado com a presença de complicações.Cholesteatoma may cause bone erosion, with high morbidity and mortality rates. Tumor Necrosis Factor -Alpha (TNF-a is one of the main cytokines involved in this process. Our goal was to evaluate the role of TNF-a in Bone Resorption and its effect on cholesteatoma. MATERIAL AND METHODS: analysis and critical literature review. RESULTS: Different studies have demonstrated that TNF-a is capable of causing bone erosion. It may stimulate the differentiation and maturation of osteoclasts or it may act on the bone matrix, exposing it to the action of the osteoclasts. It is possible to inhibit TNF-a, reducing its effects and prevent

  11. Enhanced tumor necrosis factor suppression and cyclic adenosine monophosphate accumulation by combination of phosphodiesterase inhibitors and prostanoids

    NARCIS (Netherlands)

    Sinha, B; Semmler, J; Eisenhut, T; Eigler, A; Endres, S

    1995-01-01

    We investigated cooperative effects of phosphodiesterase (PDE) inhibitors and prostanoids on cyclic adenosine monophosphate (cAMP) accumulation and tumor necrosis factor (TNF)-alpha synthesis in human peripheral blood mononuclear cells (PBMC). PDE inhibitors alone induced only a small increase in cA

  12. Modulation of tumor necrosis factor by microbial pathogens.

    OpenAIRE

    Rahman, Masmudur M.; Grant McFadden

    2006-01-01

    In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor) is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcom...

  13. Biochemical characterization and metabolic effects of the tumor necrosis factor

    OpenAIRE

    Martins e Silva, J.

    1991-01-01

    The tumor necrosis factor, preliminary identified because of its antitumor properties, refers to two kinds of similar polypeptides (TNF or cachectin, and TNF-fl or lymphotoxin), which share some biolo gical effects. Both substances, as members of the class of cytokines, play a role as mediators of inflam mation and the celiular immune response. Human cachectin is produced as a prohormone and activated by cleavage of a 76 residue peptide. Mature cachectin (with comprises 157 aminoa...

  14. Molecular mechanism of signaling by tumor necrosis factor

    Institute of Scientific and Technical Information of China (English)

    ZHA; Jikun(查纪坤); SHU; Hongbing(舒红兵)

    2002-01-01

    Tumor necrosis factor (TNF) is an important cytokine with multiple biological effects,including cell growth,differentiation,apoptosis,immune regulation and induction of inflammation. The effects of TNF are mediated by two receptors,TNF-R1 and TNF-R2. The major signal transduction pathways triggered by TNF include those that lead to apoptosis,activation of transcription factor NF-??B and protein kinase JNK. This review will discuss the molecular mechanisms of these signaling pathways.

  15. 退变腰椎Modic改变及分型与肿瘤坏死因子α、基质金属蛋白酶3的表达%Modic changing and typing of degenerative lumbar and the expression of tumor necrosis factor alpha and matrix metalloproteinase 3

    Institute of Scientific and Technical Information of China (English)

    姜世峰; 申才良; 董福龙; 张建湘; 李勇

    2012-01-01

    BACKGROUND: In recent years, a large number of reports have shown that in lumbar degenerative diseases, inflammatory cytokines play an important role, and the signals of the degenerative lumbar endplate and regional vertebral endplate are changed on MRI.OBJECTIVE: To investigate the effect of tumor necrosis factor alpha and matrix metalloproteinase 3 expression on Modic changes of lumbar endplate and the bone under endplate on MRI.METHODS: In the experimental group, 20 lumbar endplates were obtained during surgery from the patients with lumbar degeneration treated by lumbar interbody fusion. Both Modic type Ⅰ and Modic type Ⅱ contained 10 cases. As the control group, 10 lumbar endplates were also got during surgery from patients with trauma of vertebra treated with lumbar interbody fusion. The expression of tumor necrosis factor alpha and matrix metalloproteinase 3 in lumbar endplate was tested by immunohistochemical staining.RESULTS AND CONCLUSION: The positive ratio of tumor necrosis factor alpha and matrix metalloproteinase 3 in the experimental group was significantly higher than that in the control group (P < 0.05); the expressions of tumor necrosis factor alpha and matrix metalloproteinase 3 in Modic type Ⅰ were significantly higher than those in Modic type Ⅱ (P < 0.05); in the experimental group, the expression of matrix metalloproteinase 3 showed no correlation with the expression of tumor necrosis factor alpha. The expression of tumor necrosis factor alpha and matrix metalloproteinase 3 may promote vertebral endplates degeneration; there was significant difference of the tumor necrosis factor alpha and matrix metalloproteinase 3 expression between different Modic types.%背景:大量文献报道了炎性细胞因子在腰椎退变性疾病中发挥着重要的作用,并发现这些退变的腰椎终板及终板下区域椎体在MRI上出现信号的改变.目的:探讨肿瘤坏死因子α、基质金属蛋白酶3与腰椎终板及终板下骨质

  16. Correlation of MRI Biomarkers with Tumor Necrosis in Hras5 Tumor Xenograft in Athymic Rats

    Directory of Open Access Journals (Sweden)

    Daniel P. Bradley

    2007-05-01

    Full Text Available Magnetic resonance imaging (MRI can measure the effects of therapies targeting the tumor vasculature and has demonstrated that vascular-damaging agents (VDA induce acute vascular shutdown in tumors in human and animal models. However, at subtherapeutic doses, blood flow may recover before the induction of significant levels of necrosis. We present the relationship between changes in MRI biomarkers and tumor necrosis. Multiple MRI measurements were taken at 4.7 T in athymic rats (n = 24 bearing 1.94 ± 0.2-cm3 subcutaneous Hras5 tumors (ATCC 41000 before and 24 hours after clinically relevant doses of the VDA, ZD6126 (0-10 mg/kg, i.v.. We measured effective transverse relaxation rate (R2*, initial area under the gadolinium concentration-time curve (IAUGC60/150, equivalent enhancing fractions (EHF60/150, time constant (Ktrans, proportion of hypoperfused voxels as estimated from fit failures in Ktrans analysis, and signal intensity (SI in T2-weighted MRI (T2W. ZD6126 treatment induced < 90% dose-dependent tumor necrosis at 10 mg/kg; correspondingly, SI changes were evident from T2W MRI. Although R2* did not correlate, other MRI biomarkers significantly correlated with necrosis at doses of ≥ 5 mg/kg ZD6126. These data on Hras5 tumors suggest that the quantification of hypoperfused voxels might provide a useful biomarker of tumor necrosis.

  17. 阿司匹林对急性肺栓塞大鼠肿瘤坏死因子-α的干预%Intervention of aspirin on tumor necrosis factor alpha of rats with acute pulmonary embolism

    Institute of Scientific and Technical Information of China (English)

    王灵燕; 周仁芳; 王灵聪

    2014-01-01

    Objective To explore the intervention of aspirin on tumor necrosis factor alpha (TNF-α) of rats with acute pulmonary (APE). Methods A total of 64 rats were randomly divided into 4 groups which were normal group(control), sham operation group(sham), model group(model) and aspirin group(aspirin) with 16 rats in each. The autologous blood clot were token to copy the APE animal mode. The serum TNF-αand the mRNA expression level of lung tissue were com-pared at 4-hour versus 72-hour after modeling. Results At 4-hour and 72-hour post-embolization, the control group and sham group showed normal lung tissue, the lung tissue of model group was significantly associated with alveolar wall con-gestion, emphysema, mild edema and inflammatory cells infiltration. At 4-hour after modeling, the degree of lung tissue lesion in the aspirin group was lighter than in the model group, the main lesions was alveolar wall edema while at 72-hour after modeling, the main pathological changes in lung tissue was mild or moderate hyperemia of alveolar walls, edema and inflammatory cell infiltration. The serum TNF-αamong four groups were significantly different at 4-hour and 72-hour after modeling (F=6.59, 23.09, P<0.05). The further multiple comparison showed that the level of serum TNF-α in aspirin group was significantly higher than those in the control group, sham group and model group at 4-hour after modeling (t=4.38,2.67,2.90,P<0.05). The levels of serum TNF-α in model was significantly higher than the control group, sham group and aspirin group at 72-hour af-ter modeling(t=5.43,7.37,6.64,P<0.05). The TNF-αmRNA among four groups were significantly differ-ent at 4-hour and 72-hour after modeling (F=39.35, 72.05,P<0.05). The TNF-α mRNA expression in lung tissue of the model group were significantly higher than those in control group, sham group and aspirin group at 4- hour and 72-hour after modeling(t=9.72, 8.36, 8.24; 12.12, 12.04, 11.85, P<0.05). Conclusion Aspirin can play an

  18. Diagnostic and prognostic value of serum nitric oxide, tumor necrosis factor-alpha, basic fibroblast growth factor and copper as angiogenic markers in premenopausal breast cancer patients: a case-control study.

    Science.gov (United States)

    Hewala, T I; Abd El-Moneim, N A; Ebied, S Abd El-Moneim; Sheta, M I; Soliman, K; Abu-Elenean, A

    2010-01-01

    Many studies demonstrate that increased microvessel density (MVD) surrounding primary tumour is associated with decreased overall survival in patients with breast cancer. This study compares the diagnostic and prognostic values of the angiogenic serum factors nitric oxide (NO), tumour necrosis factor-alpha (TNFalpha), basic fibroblast growth factor (bFGF) and copper with those of serum CA15-3 as the standard tumour marker in breast cancer patients. Microvessel density was estimated in CD31-immunostained sections from breast cancer patients. Before surgery, NO, TNFalpha, bFGF, copper and CA 15-3 were measured in serum samples from 30 premenopausal breast cancer patients in comparison with 15 healthy controls. The diagnostic values of the assayed parameters were compared using receiver operating characteristic (ROC) curve analysis. Univariate survival analysis of patients was assessed using the Kaplan-Meier method. Breast cancer tissues showed higher MVD than did normal breast tissues adjacent to the tumour (P = 0.008). Before surgery, tumour MVD correlated significantly with serum NO, TNFalpha, bFGF and copper (r = 0.458, P = .011; r = 0.379, P = .039; r = 0.513, P = .004 and r = 0.613, P = 0.000, respectively). Serum NO, TNFalpha, bFGF, copper and CA 15-3 levels in patients were significantly elevated compared with controls (P = 0.011, P = 0.004, P = 0.039, P = 0.000 and P = 0.001, respectively). Kaplan-Meier analysis revealed that patients with elevated serum TNFalpha, CA 15-3 and copper (P = 0.035, P = 0.040, P = 0.0339, respectively) had an overall survival significantly shorter than those who had lower levels of these parameters. These data suggest that serum TNFalpha, CA 15-3 and copper are useful predictive markers for overall survival in premenopausal breast cancer patients.

  19. Monocyte-mediated tumoricidal activity via the tumor necrosis factor-related cytokine, TRAIL.

    Science.gov (United States)

    Griffith, T S; Wiley, S R; Kubin, M Z; Sedger, L M; Maliszewski, C R; Fanger, N A

    1999-04-19

    TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a molecule that displays potent antitumor activity against selected targets. The results presented here demonstrate that human monocytes rapidly express TRAIL, but not Fas ligand or TNF, after activation with interferon (IFN)-gamma or -alpha and acquire the ability to kill tumor cells. Monocyte-mediated tumor cell apoptosis was TRAIL specific, as it could be inhibited with soluble TRAIL receptor. Moreover, IFN stimulation caused a concomitant loss of TRAIL receptor 2 expression, which coincides with monocyte acquisition of resistance to TRAIL-mediated apoptosis. These results define a novel mechanism of monocyte-induced cell cytotoxicity that requires TRAIL, and suggest that TRAIL is a key effector molecule in antitumor activity in vivo.

  20. Treatment with tumor necrosis factor inhibitors in axial spondyloarthritis

    DEFF Research Database (Denmark)

    Ciurea, A.; Weber, U.; Stekhoven, D.

    2015-01-01

    Objective. To evaluate the initiation of and response to tumor necrosis factor (TNF) inhibitors for axial spondyloarthritis (axSpA) in private rheumatology practices versus academic centers. The Journal of Rheumatology, Methods.We compared newly initiated TNF inhibition for axSpA in 363 patients...... was slightly higher in the hospital setting. Mean levels (+/- SD) of the Ankylosing Spondylitis Disease Activity Score were, however, virtually identical in private practices and academic centers (3.4 +/- 1.0 vs 3.4 +/- 0.9, p = 0.68). An Assessment of SpondyloArthritis international Society (ASAS40) response...

  1. Risk of infection in monotherapy with tumor necrosis factor alpha inhibitor: a Meta-analysis%肿瘤坏死因子α抑制剂单药疗法致感染风险的Meta分析

    Institute of Scientific and Technical Information of China (English)

    李文思; 吕迁洲; 陈璋璋

    2015-01-01

    Objective To evaluate the risk of infection in monotherapy of tumor necrosis factor alpha (TNF-α) inhibitor.Methods The database of Pubed, Embase, Cochrane library, and Web with Science were searched from the inception to November, 2014.The literatures of randomized controlled trials in English which included reports that only used TNF-α inhibitor (the test group) and placebo or positive controlled drug (the control group) were selected.The methodological quality of the literatures which enrolled into the study were assessed by Jadad scale (inferior quality: < 3 points, high quality: 3-5 points).The software RevMan 5.2 was used for Meta-analysis.The infection rate and the severe infection rate were expressed by relative risk (RR), Peto odds ratio (Peto OR)and 95 % confidence interval (CI).Results A total of 33 trials presented by 32 reports, and 11 819 patients (7 408 cases in the test group using adalimumab or golimumab or infliximab or etanercept, respectively, and 4 411 cases in the control group using placebo, positive control drug such as methotrexate or salazosulfapyridine, respectively) were enrolled into the Meta-analysis.The Jadad scores of the 33 trials were all ≥ 3 points.The results of the Meta-analysis showed that the overall total incidence of infection in patients who used TNF-α inhibitors only was higher than that in the patients who used placebo [33.03% (1 702/5 153) vs.29.53% (873/2 956), RR =1.17, 95% CI: 1.09-1.25, P <0.000 01].There was no significant difference in the overall incidence of infection between the test group and the positive controlled drug group [50.1% (362/723)vs.48.3% (320/662), RR =1.10, 95% CI: 0.90-1.34, P =0.36].There were no significant differences in the incidence of severe infection between the test group and the placebo control group, the positive controlled drug group [1.4% (73/5 067)vs.1.7% (48/2 902), Peto OR =0.90, 95% CI: 0.61-1.32, P =0.46;2.4% (34/1 410) vs.2.8% (28/976), RR =1

  2. Leukotriene B4 and tumor necrosis factor release from leukocytes: effect of peritoneal dialysate.

    Science.gov (United States)

    Jörres, A; Jörres, D; Gahl, G M; Kessel, M; Müller, C; Köttgen, E; Serke, S; Schulz, E; Mahiout, A

    1991-01-01

    The effect of peritoneal dialysate on the capacity of peripheral blood polymorphonuclear (PMNL) and mononuclear leukocytes (MNC) to release leukotriene B4 (LTB4) and tumor necrosis factor alpha (TNF alpha) was investigated in vitro. Following density gradient separation, aliquots of 5 x 10(6) PMNL or MNC were incubated in peritoneal dialysis fluid containing 1.5% glucose or Hanks' buffer (= control) for 1-2 h at 37 degrees C. TNF alpha and LTB4 production was stimulated with Escherichia coli lipopolysaccharide (LPS) and calcium ionophore A23187, respectively. MNC incubated in buffer and LPS produced (mean +/- SD) 1,006 +/- 522 pg TNF alpha/5 x 10(6) cells; no significant amounts of TNF alpha were detectable in the presence of dialysate. An inhibition of TNF alpha release was also observed in MNC exposed to bicarbonate-buffered dialysates (pH 7.40) and 4.25% and 1.5% glucose solution with physiologic osmolality. Incubation of PMNL in Hanks' buffer followed by A23187 stimulation led to production of 29.1 +/- 19.2 ng LTB4/5 x 10(6) cells, whereas glucose-incubated cells were refractory to ionophore stimulation (less than 0.1 ng LTB4/5 x 10(6) cells). The failure of dialysate-exposed leukocytes to release inflammatory mediators in response to adequate stimuli may contribute to the impairment of cellular host defense in the setting of continuous ambulatory peritoneal dialysis.

  3. Responses of serum inflammatory factor high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha in elderly males with cerebral infarction Non-randomized concurrent control

    Institute of Scientific and Technical Information of China (English)

    Guiping Jiao; Xinjie Tan; Zhiliu Yuan; Chunling Li; Jing Wang; Wen Mo

    2008-01-01

    BACKGROUND: Cerebral infarction is poorly treated due to neuronal necrosis and secondary pathophysiological changes; for example, free radical production and inflammatory reactions.OBJECTIVE: To detect the levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor nccrosis factor-α (TNF-α) in elderly males with cerebral infarction.DESIGN: Non-randomized current control study.SETTING: Cadre Medical Department, Guizhou Provincial People's Hospital.PARTICIPANTS: Forty elderly males (65-89 years old) with cerebral infarction were selected from Cadre Medical Department, Guizhou Provincial People's Hospital from February 2004 to December 2006. All patients met the diagnostic criteria of cerebral infarction modified at the 4th National Cerebrovascular Disease Academic Meeting, and were diagnosed on the basis of CT or MRI tests. Furthermore, 35 elderly male inpatients (65-87 years old) without cerebral infarction were selected as the control group. Included subjects provided confirmed consent and did not have heart disease, diabetes mellitus, lipid disorder, acute trauma, infection, rheumatism, or other inflammatory diseases. The study was approved by the local ethics committee. There were no significant differences in age, blood pressure, and lipid levels between the cerebral infarction group and the control group (P>0.05), and this suggested that the baseline data of both groups were comparable.METHODS: Fasting venous blood was drawn from cerebral infarction patients 24 hours after cerebral infarction attack and from control subjects 24 hours after hospitalization. A latex-enhanced immunoturbidimetric assay and an enzyme-linked immunosorbent assay were used to detect the levels of hs-CRP, IL-6, and TNF-α in the serum.MAIN OUTCOME MEASURES: The levels of hs-CRP, IL-6, and TNF-α in the serum in both groups.RESULTS: Forty cerebral infarction patients and thirty-five control subjects were included in the final analysis without any loss

  4. IgE low affinity receptor (CD23) expression, Plasmodium falciparum specific IgE and tumor necrosis factor-alpha production in Thai uncomplicated and severe falciparum malaria patients.

    Science.gov (United States)

    Kumsiri, Ratchanok; Troye-Blomberg, Marita; Pattanapanyasat, Kovit; Krudsood, Srivicha; Maneerat, Yaowapa

    2016-02-01

    Previous studies have suggested that Plasmodium falciparum (P. falciparum) specific IgE in the form of immune complexes crosslinking the low-affinity receptor (CD23) on monocyte results in tumor necrosis factor (TNF)-α and nitric oxide (NO) production. However, the roles of these parameters in severity and immune protection are still unclear. This study aimed to determine the association between CD23 expression on monocytes, plasma soluble CD23 (sCD23), total IgE, malaria-specific IgE and IgG, and TNF-α levels in P. falciparum infected patients. We evaluated 64 uncomplicated (UC) and 25 severe patients (S), admitted at the Hospital for Tropical Diseases, Mahidol University, and 34 healthy controls (C) enrolled in 2001. Flow cytometry and enzyme linked immunosorbent assays (ELISA) demonstrated that trends of the CD23 expression, levels of sCD23 and specific IgE were higher in the S group as compared to those in the UC and C groups. Plasma levels of P. falciparum specific IgE in the UC (p=0.011) and S groups (p=0.025) were significantly higher than those in C group. In contrast the TNF-α levels tended to be higher in the UC than those in the S (p=0.343) and significantly higher than those in C (p=0.004) groups. The specific IgG levels in UC were significantly higher than those in S and C (pIgE-IgG complexes (r=-0.715, p=0.002). Significant positive correlations between levels of specific IgE and TNF-α (r=0.575, p=0.010); and sCD23 (r=0.597, p=0.000) were also observed. In conclusion, our data suggest that CD23 expression and malaria-specific IgE levels may be involved in the severity of the disease while TNF-α and the malaria-specific IgG may correlate with protection against falciparum malaria.

  5. Tumor necrosis factor inhibitors block apoptosis of human epithelial cells of the salivary glands.

    Science.gov (United States)

    Sisto, Margherita; D'Amore, Massimo; Caprio, Simone; Mitolo, Vincenzo; Scagliusi, Pasquale; Lisi, Sabrina

    2009-08-01

    Inhibition of tumor necrosis factor-alpha (TNF-alpha) in organ-specific autoimmune disease is proving efficacious for a large number of patients. A wide array of biological agents has been designed to inhibit TNF-alpha, such as adalimumab (fully humanized) and etanercept (soluble TNF-alpha receptor fusion constructs p75 subunit). Recently, we suggested that anti-Ro and anti-La autoantibodies (Abs) isolated from patients with Sjögren's syndrome, an autoimmune rheumatic disease, are able to trigger cell death through extrinsic apoptotic mechanisms in human salivary gland epithelial cells (SGEC). We analyzed if primary human SGEC cultures, established from biopsy of labial minor salivary glands, are able to produce TNF-alpha, an inductor of the extrinsic apoptotic pathway, when treated with anti-Ro autoantibodies. A comparative study was performed to test the efficacy of adalimumab and etanercept to block TNF-alpha-mediated apoptosis. ELISA assay and RT-PCR were employed to visualize TNF-alpha production, and apoptosis was evaluated by DNA ladder and flow cytometry. We found that cell treatment with anti-Ro autoantibodies determines TNF-alpha production that reaches a maximum at 16 h and is decreased (P < 0.05) at 24 and 48 h. Adalimumab seems to be more efficacious than etanercept in blocking TNF-alpha-mediated apoptosis. The YOPRO-1 (+) and propidium iodide (-) method revealed 60% of apoptotic cells after 24 h of incubation with anti-Ro compared with 15% of apoptotic cells treated with anti-Ro plus adalimumab and 25% of apoptotic cells treated with anti-Ro plus etanercept. The antiapoptotic effect of adalimumab and etanercept was supported by inhibition of DNA laddering induced by anti-Ro Abs. These data validate the therapeutic efficacy of the anti-TNF reagents in the treatment of autoimmune disorders.

  6. Tumor necrosis factor and the pathogenesis of Pichinde virus infection in guinea pigs.

    Science.gov (United States)

    Aronson, J F; Herzog, N K; Jerrells, T R

    1995-03-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage-adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. Tumor necrosis factor was found in the spleens of adPIC- and PIC3739-infected animals in week 1 of infection; TNF alpha mRNA levels in spleens and livers of adPIC infected animals increased and remained high throughout infection, whereas PIC3739-infected organs showed down regulation of TNF alpha mRNA late in infection. Peritoneal macrophages explanted from adPIC-infected animals showed enhanced lipopolysaccharide-inducible TNF production. Altered regulation of TNF production may play a role in the pathogenesis of guinea pig arenavirus disease.

  7. Herceptin conjugates linked by EDC boost direct tumor cell death via programmed tumor cell necrosis.

    Directory of Open Access Journals (Sweden)

    Jiemiao Hu

    Full Text Available Tumor-targeted antibody therapy is one of the safest biological therapeutics for cancer patients, but it is often ineffective at inducing direct tumor cell death and is ineffective against resistant tumor cells. Currently, the antitumor efficacy of antibody therapy is primarily achieved by inducing indirect tumor cell death, such as antibody-dependent cell cytotoxicity. Our study reveals that Herceptin conjugates, if generated via the crosslinker EDC (1-ethyl-3-(3-dimethylaminopropyl carbodiimide hydrochloride, are capable of engendering human epidermal growth factor receptor 2 (Her2 positive tumor cells death. Using a high-performance liquid chromatography (HPLC system, three peaks with estimated molecular weights of antibody monomer, dimer, and trimer were isolated. Both Herceptin trimer and dimer separated by HPLC induced significant levels of necrotic tumor cell death, although the trimer was more effective than the dimer. Notably, the Herceptin trimer also induced Herceptin-resistant tumor cell death. Surprisingly different from the known cell death mechanism that often results from antibody treatment, the Herceptin trimer elicited effective and direct tumor cell death via a novel mechanism: programmed cell necrosis. In Her2-positive cells, inhibition of necrosis pathways significantly reversed Herceptin trimer-induced cell death. In summary, the Herceptin trimer reported herein harbors great potential for overcoming tumor cell resistance to Herceptin treatment.

  8. 抗肿瘤坏死因子-α拮抗剂在SAPHO综合征治疗中的应用%Tumor Necrosis Factor-alpha Blockers in SAPHO Syndrome

    Institute of Scientific and Technical Information of China (English)

    李忱; 李菁; 董振华; 刘晋河

    2013-01-01

    目的 SAPHO综合征属罕见病,尚缺乏统一的治疗方案,本文旨在探讨抗肿瘤坏死因子-α拮抗剂在本病治疗中的作用.方法 对8例难治性SAPHO综合征患者的临床资料、治疗及转归进行分析并复习相关文献.结果 8例患者均为女性.7例表现为掌跖脓疱病,1例无皮肤损害.骨关节受累中上胸壁处受累8例,外周关节受累6例,骶髂关节受累6例,脊柱关节受累2例.8例患者均给予非甾体抗炎药(NSAID)、糖皮质激素和(或)改变病情抗风湿药(DMARD)和(或)双磷酸盐,症状均无改善,后加用抗肿瘤坏死因子-α拮抗剂,症状均改善.但在治疗过程中,1例出现皮疹加重,1例出现颌下腺炎;4例停药后复发;3例配合中药治疗,症状均不同程度改善.结论 抗肿瘤坏死因子-α可显著改善SAPHO综合征的症状,但个别患者出现皮疹加重,有潜在的感染风险,且停药后易复发;中医药治疗本病有一定作用,有望成为治疗本病的新方法.%Objective Synovitis, acne, pustulosis, hyperostosis, osteitis ( SAPHO) syndrome is a very rare disease and still lack standardized therapy. We analyzed the clinical efficacy of anti - tumor necrosis factor - α ( TNF -α) inhibitor therapy in treatment of SAPHO syndrome. Methods We analyzed 8 patients with refractory SAPHO syndrome treating with anti - TNF - α inhibitors, and reviewed cases treating with anti - TNF -α inhibitors reported in the literature. Results Eight patients were all female:7 of them had palmoplantar pustulosis, the other one was free of skin lesions. Their osteoarticular manifestations included anterior chest wall involving in 8 patients,peripheral joints involving in 6 patients, sacroiliac joints involving in 6 patients, and vertebral joints involving in 2 patients. All patients were treated with non - steroidal anti - inflammatory drugs ( NSAIDs) as the first - line therapy, and corticosteroid and ( or) disease modifying anti - rheumatic drugs

  9. Tumor necrosis factor and cancer, buddies or foes?

    Institute of Scientific and Technical Information of China (English)

    Xia WANG; Yong LIN

    2008-01-01

    Tumor necrosis factor (TNF) is a multifunctional cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory eytokine, TNF is secreted by inflammatory cells, which may be involved in inflammation-associated carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK). NF-κB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the NF-κB and JNK is involved in determining cellular outcomes in response to TNF. In regard to cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous tumor promoter, because TNF stimulates the growth, proliferation, invasion and metastasis, and tumor angiogenesis of cancer cells. On the other hand, TNF could be a cancer killer. The property of TNF in inducing cancer cell death renders it a potential cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing cancer cells to TNF-induced apoptosis through inhibiting survival signals such as NF-κB, by combined therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in cancer biology with specific emphasis on carcinogenesis and cancer therapy.

  10. Soluble and cell surface receptors for tumor necrosis factor

    DEFF Research Database (Denmark)

    Wallach, D; Engelmann, H; Nophar, Y

    1991-01-01

    Tumor necrosis factor (TNF) initiates its multiple effects on cell function by binding at a high affinity to specific cell surface receptors. Two different molecular species of these receptors, which are expressed differentially in different cells, have been identified. The cDNAs of both receptor...... have recently been cloned. Antibodies to one of these receptor species (the p55, type I receptor) can trigger a variety of TNF like effects by cross-linking of the receptor molecules. Thus, it is not TNF itself but its receptors that provide the signal for the response to this cytokine...... in certain pathological situations. Release of the soluble receptors from the cells seems to occur by proteolytic cleavage of the cell surface forms and appears to be a way of down-regulating the cell response to TNF. Because of their ability to bind TNF, the soluble receptors exert an inhibitory effect...

  11. Endotoxemia por lipopolissacarídeo de Escherichia coli, em eqüinos: efeitos de antiinflamatórios nas concentrações sérica e peritoneal do fator de necrose tumoral alfa (TNF-alfa Escherichia coli lipopolisacharide (LPS induced endotoxemia in horses: effects of anti-inflammatory drugs on seric and peritoneal tumor necrosis factor alpha (TNF-alpha concentrations

    Directory of Open Access Journals (Sweden)

    R.C. Campebell

    2007-08-01

    Full Text Available Avaliou-se a inibição da produção do fator de necrose tumoral alfa (TNF-alfa devido ao pré-tratamento com antiinflamatório esteroidal (dexametasona e não esteroidal (diclofenaco sódico em eqüinos com endotoxemia induzida experimentalmente. Foram utilizados 15 cavalos machos não castrados, distribuídos em três grupos de cinco animais: controle (C, diclofenaco sódico (DS e dexametasona (DM. A endotoxemia subletal foi induzida pela infusão intravenosa (IV de 0,1mg/kg/pv de lipopolissacarídeo (LPS de Escherichia coli 055:B5, administrado em 250ml de solução estéril de cloreto de sódio a 0,9%, durante 15min. Os cavalos do grupo-controle foram tratados com solução de cloreto de sódio a 9% IV. Nos animais do grupo DS, administraram-se, por via oral, 2,2mg/kg de diclofenaco sódico e, nos do grupo DM, 1,1mg/kg de dexametasona IV, respectivamente, 60 e 30min antes da infusão da endotoxina. Mensurou-se, por meio de ensaio de toxicidade com células da linhagem L929, a concentração de TNF-alfa no soro e no líquido peritoneal às 0, 1¼, 3 e 6 horas após injeção do LPS. No grupo-controle, observou-se aumento significativo de TNF-alfa sérico, em relação ao valor basal e aos grupos DS e DM, 1,15 horas após a indução da endotoxemia. No líquido peritoneal, as concentrações observadas estavam abaixo daquelas da curva padrão de TNF-alfa, não havendo diferença entre os grupos (P>0,05.The inhibition of tumor necrosis factor alpha (TNF-alpha production due to pre-treatment with steroidal (dexamethazone and non-steroidal (sodium diclofenac anti-inflammatories was studied in horses under experimentally induced endotoxemy. Fifteen stallions were allotted into three groups of five animals each: control (C, sodium diclofenac (SD and dexamethazone (DM. Sublethal endotoxemy was induced with 0.1mg/kg/bw Escherichia coli 055:B5 lipopolysaccharide (LPS, IV, administrated in 250ml of 0.9% sterile sodium chloride, during 15 minutes

  12. Retrovirus-mediated gene transfer of the cytokine genes interleukin-1beta and tumor necrosis factor-alpha into human neuroblastoma cells: consequences for cell line behavior and immunomodulatory properties.

    Science.gov (United States)

    Coze, C; Leimig, T; Jimeno, M T; Mannoni, P

    2001-03-01

    We have investigated the value of a gene therapy approach for neuroblastoma (NB), based on retroviral transduction of the IL-1beta or TNF-alpha cytokine genes into human NB lines. Secretion of the corresponding cytokine, was demonstrated in all lines, although with considerable quantitative variations. Cytokine gene expression significantly reduced the proliferation index (p = 0.0001); this effect was associated with either terminal neuronal (one TNF-alpha line) or fibroblast-like differentiation (two IL-1beta lines), leading to growth arrest after a few weeks. Cell surface levels of CD54 and HLA class II remained unaffected, but HLA class I (p < 0.001) and CD58 expression (p = 0.01) increased on SKNSH after TNF-alpha gene transfer. Mononuclear cells from normal allogeneic donors cocultured with both IL-1beta (p < 0.001) and TNF-alpha lines (p < 0.01), showed a significant increase in the proportion of activated T cells (CD3+DR+); however, their cytotoxicity and proliferation rate remained unchanged. Immunotherapy of neuroblastoma will require identification of transduced lines in which cytokine secretion induces phenotypic changes in such a way as to augment their likely immunomodulatory properties without impeding cell growth. Because of the limited efficacy of IL-1beta or TNF-alpha gene transfer alone, further studies should focus on combination with other immunomodulatory agents, to improve their potential efficacy in neuroblastoma.

  13. Requirement for Tumor Necrosis Factor Receptor 2 Expression on Vascular Cells To Induce Experimental Cerebral Malaria

    OpenAIRE

    Stoelcker, Benjamin; Hehlgans, Thomas; Weigl, Karin; Bluethmann, Horst; Grau, Georges E.; Männel, Daniela N

    2002-01-01

    Using tumor necrosis factor receptor type 2 (TNFR2)-deficient mice and generating bone marrow chimeras which express TNFR2 on either hematopoietic or nonhematopoietic cells, we demonstrated the requirement for TNFR2 expression on tissue cells to induce lethal cerebral malaria. Thus, TNFR2 on the brain vasculature mediates tumor necrosis factor-induced neurovascular lesions in experimental cerebral malaria.

  14. Role of mononuclear phagocyte function in endotoxin-induced tumor necrosis

    NARCIS (Netherlands)

    Hofhuis, F.M.A.; Bloksma, N.; Willers, J.M.N.

    1984-01-01

    The temporal susceptibility of tumors to induction of necrosis and regression by endotoxin was investigated further with a focus on the role of the putative mediator, tumor necrosis factor (TNF). Production of this factor was shown earlier to require prior activation of the mononuclear phagocytic sy

  15. Affinity Purification of Tumor Necrosis Factor-α Expressed in Raji Cells by Produced scFv Antibody Coupled CNBr-Activated Sepharose

    OpenAIRE

    2013-01-01

    Purpose: Recombinant tumor necrosis factor-alpha (TNF-α) has been utilized as an antineoplastic agent for the treatment of patients with melanoma and sarcoma. It targets tumor cell antigens by impressing tumor-associated vessels. Protein purification with affinity chromatography has been widely used in the downstream processing of pharmaceutical-grade proteins. Methods: In this study, we examined the potential of our produced anti-TNF-scFv fragments for purification of TNF-α produced by Raj...

  16. Tumor necrosis factor-alpha increases in vitro blood brain barrier permeability%肿瘤坏死因子α对体外血脑屏障模型通透性的影响

    Institute of Scientific and Technical Information of China (English)

    彭镜; 尹飞; 曾卫民; 甘娜; 张红媛

    2007-01-01

    死因子α的作用,自120 min后,Y-27632预处理组与Y-27632对照组比较,差异也有显著性意义(P<0.05).结论:肿瘤坏死因子α可导致血脑屏障通透性增高,Y-27632预处理能早期逆转肿瘤坏死因子α对血脑屏障通透性的影响.%BACKGROUND:The levels of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are increased during infectious brain edema, and are positively relevant to the degree of brain damage. However, whether TNF-α can enhance blood brain barrier (BBB) permeability remains unclear, especially in vitro.OBJECTIVE: To understand the changes and possible mechanism of the BBB permeability induced by TNF-α in vitro.DESIGN: Randomized controlled cell model study in vitro.SETTING:Department of Pediatrics, Xiangya Hospital, Central South University; Department of Biochemistry, Xiangya Medical College, Central South University.MATERIALS: Twenty 7-day-old healthy Sprague-Dawley rats, of clean grade and either gender, were provided by the Animal Center, Xiangya Hospital, Central South University. TNF-α was purchased from sigma Company; DMEM fluid medium and fetal bovine serum were purchased from Hyclone Company; Y-27632 was purchased from Alexis Company,and rabbit anti-human factor Ⅷ -related antigen was purchased from Zymed Company; Mouse anti-rat glial fibrillary acidic protein (GFAP) was purchased from Neomarkers. Other biochemical reagents were imported (Sigma Company).METHODS: This experiment was carried out in the Xiangya Hospital, Central South University between March 2004 and April 2005. Brain microvascular endothelial cells and astrocytes were co-cultured 10 days to set up rat models of BBB in vitro. Then, the cells were divided into 4 groups: model group(BBB models were prepared), TNF-α group ( BBB model incubated with 0.01 g/L TNF-α for 5 hours), Y-27632 pretreated group ( BBB model incubated with 30 μmol/L Y-27632 for 1 hour before 0.01g/L TNF-α challenge ) and Y-27632 control group (BBB models only incubated with Y-27632

  17. alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis.

    Science.gov (United States)

    Dimberg, Anna; Rylova, Svetlana; Dieterich, Lothar C; Olsson, Anna-Karin; Schiller, Petter; Wikner, Charlotte; Bohman, Svante; Botling, Johan; Lukinius, Agneta; Wawrousek, Eric F; Claesson-Welsh, Lena

    2008-02-15

    Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.

  18. Tumor necrosis factor beta and ultraviolet radiation are potent regulators of human keratinocyte ICAM-1 expression

    Energy Technology Data Exchange (ETDEWEB)

    Krutmann, J.; Koeck, A.S.; Schauer, E.; Parlow, F.; Moeller, A.K.; Kapp, A.; Foerster, E.S.; Schoepf, E.L.; Luger, T.A. (Univ. of Freiburg (Germany, F.R.))

    1990-08-01

    Intercellular adhesion molecule-1 (ICAM-1) functions as a ligand of leukocyte function-associated antigen-1 (LFA-1), as well as a receptor for human picorna virus, and its regulation thus affects various immunologic and inflammatory reactions. The weak, constitutive ICAM-1 expression on human keratinocytes (KC) can be up-regulated by cytokines such as interferon-gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). In order to further examine the regulation of KC ICAM-1 expression, normal human KC or epidermoid carcinoma cells (KB) were incubated with different cytokines and/or exposed to ultraviolet (UV) radiation. Subsequently, ICAM-1 expression was monitored cytofluorometrically using a monoclonal anti-ICAM-1 antibody. Stimulation of cells with recombinant human (rh) interleukin (IL) 1 alpha, rhIL-4, rhIL-5, rhIL-6, rh granulocyte/macrophage colony-stimulating factor (GM-CSF), rh interferon alpha (rhIFN alpha), and rh transforming growth factor beta (TGF beta) did not increase ICAM-1 surface expression. In contrast, rhTNF beta significantly up-regulated ICAM-1 expression in a time- and dose-dependent manner. Moreover, the combination of rhTNF beta with rhIFN gamma increased the percentage of ICAM-1-positive KC synergistically. This stimulatory effect of rhTNF beta was further confirmed by the demonstration that rhTNF beta was capable of markedly enhancing ICAM-1 mRNA expression in KC. Finally, exposure of KC in vitro to sublethal doses of UV radiation (0-100 J/m2) prior to cytokine (rhIFN tau, rhTNF alpha, rhTNF beta) stimulation inhibited ICAM-1 up-regulation in a dose-dependent fashion. These studies identify TNF beta and UV light as potent regulators of KC ICAM-1 expression, which may influence both attachment and detachment of leukocytes and possibly viruses to KC.

  19. Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice

    OpenAIRE

    Knight, Belinda; Yeoh, George C.T.; Husk, Kirsten L.; Ly, Tina; Abraham, Lawrence J; Yu, Changpu; Rhim, Jonathan A.; Fausto, Nelson

    2000-01-01

    Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TN...

  20. Prognostic value of tumor necrosis at CT in diffuse large B-cell lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Adams, Hugo J.A., E-mail: h.j.a.adams@gmail.com [Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht (Netherlands); Klerk, John M.H. de [Department of Nuclear Medicine, Meander Medical Center, Amersfoort (Netherlands); Fijnheer, Rob [Department of Hematology, Meander Medical Center, Amersfoort (Netherlands); Dubois, Stefan V. [Department of Pathology, Meander Medical Center, Amersfoort (Netherlands); Nievelstein, Rutger A.J.; Kwee, Thomas C. [Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Utrecht (Netherlands)

    2015-03-15

    Highlights: •CT is compulsory for staging newly diagnosed DLBCL. •Approximately 13.7% of DLBCL patients have tumor necrosis at CT. •Tumor necrosis status at CT is not associated with any NCCN-IPI factor. •Patients with tumor necrosis at CT have a significantly worse outcome. -- Abstract: Objective: To determine the prognostic value of tumor necrosis at computed tomography (CT) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Materials and methods: This retrospective study included 51 patients with newly diagnosed DLBCL who had undergone both unenhanced and intravenous contrast-enhanced CT before R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone) chemo-immunotherapy. Presence of tumor necrosis was visually and quantitatively assessed at CT. Associations between tumor necrosis status at CT and the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI) factors were assessed. Cox regression analysis was used to determine the prognostic impact of NCCN-IPI scores and tumor necrosis status at CT. Results: There were no correlations between tumor necrosis status at CT and the NCCN-IPI factors categorized age (ρ = −0.042, P = 0.765), categorized lactate dehydrogenase (LDH) ratio (ρ = 0.201, P = 0.156), extranodal disease in major organs (φ = −0.245, P = 0.083), Ann Arbor stage III/IV disease (φ = −0.208, P = 0.141), and Eastern Cooperative Oncology Group (ECOG) performance status (φ = 0.015, P = 0.914). In the multivariate Cox proportional hazards model, only tumor necrosis status at CT was an independent predictive factor of progression-free survival (P = 0.003) and overall survival (P = 0.004). Conclusion: The findings of this study indicate the prognostic potential of tumor necrosis at CT in newly diagnosed DLBCL.

  1. Induction of tumor necrosis factor expression and resistance in a human breast tumor cell line.

    OpenAIRE

    Spriggs, D; Imamura, K; Rodriguez, C; Horiguchi, J; Kufe, D W

    1987-01-01

    Tumor necrosis factor (TNF) is a polypeptide cytokine that is cytotoxic to some but not all tumor cells. The basis for resistance to the cytotoxic effects of this agent remains unclear. We have studied the development of TNF resistance in human ZR-75-1 breast carcinoma cells. ZR-75-1 cells have undetectable levels of TNF RNA and protein. However, TNF transcripts are transiently induced in these cells by exposure to recombinant human TNF. This induction of TNF RNA is associated with production...

  2. Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor.

    Science.gov (United States)

    Farma, Jeffrey M; Puhlmann, Markus; Soriano, Perry A; Cox, Derrick; Paciotti, Giulio F; Tamarkin, Lawrence; Alexander, H Richard

    2007-06-01

    Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.

  3. Soluble tumour necrosis factor receptor release after anti-CD3 monoclonal antibody treatment in mice is independent of tumour necrosis factor-alpha release.

    NARCIS (Netherlands)

    Vossen, A.C.T.M.; Tibbe, G.J.M.; Buurman, W.A.; Benner, R.; Savelkoul, H.F.J.

    1996-01-01

    Soluble tumour necrosis factor receptor release after anti-CD3 monoclonal antibody treatment in mice is independent of tumour necrosis factor-alpha release. Vossen AC, Tibbe GJ, Buurman WA, Benner R, Savelkoul HF. Department of Immunology, Erasmus University, Rotterdam, The Netherlands. The involvem

  4. Reduction of Burn Progression with Topical Delivery of (Antitumor Necrosis Factor-alpha )-Hyaluronic Acid Conjugates

    Science.gov (United States)

    2012-01-01

    level of hair follicle cell apoptosis within 24 hours of the initial burn injury.27 Intravenous injection of semapimod, a selective inhibitor of...effect of such treat- ment was unclear. Singer and coworkers have also demonstrated 30% reduction in depth of hair follicle necrosis after systemic...whether topical application of antibodies targeting tumor necrosis factor-a (TNF-a) or interleukin-6 (IL-6) conjugated to hyaluronic acid (HA) could

  5. The Tumor Necrosis Factor Superfamily of Cytokines in the Inflammatory Myopathies: Potential Targets for Therapy

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2012-01-01

    Full Text Available The idiopathic inflammatory myopathies (IM represent a heterogeneous group of autoimmune diseases, of which dermatomyositis (DM, polymyositis (PM, and sporadic inclusion body myositis (IBM are the most common. The crucial role played by tumor necrosis factor alpha (TNFα in the IM has long been recognized. However, so far, 18 other members of the TNF superfamily have been characterized, and many of these have not yet received the attention they deserve. In this paper, we summarize current findings for all TNF cytokines in IM, pinpointing what we know already and where current knowledge fails. For each TNF family member, possibilities for treating inflammatory diseases in general and the IM in particular are explored.

  6. Tumor Necrosis Factor-α -and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

    Science.gov (United States)

    Ott, Lee W.; Resing, Katheryn A.; Sizemore, Alecia W.; Heyen, Joshua W.; Cocklin, Ross R.; Pedrick, Nathan M.; Woods, H. Cary; Chen, Jake Y.; Goebl, Mark G.; Witzmann, Frank A.; Harrington, Maureen A.

    2010-01-01

    The pro-inflammatory cytokines, Tumor Necrosis Factor-alpha (TNFα) and Interleukin-1 (IL-1) mediate the innate immune response. Dysregulation of the innate immune response contributes to the pathogenesis of cancer, arthritis, and congestive heart failure. TNFα- and IL-1-induced changes in gene expression are mediated by similar transcription factors; however, TNFα and IL-1 receptor knock-out mice differ in their sensitivities to a known initiator (lipopolysaccharide, LPS) of the innate immune response. The contrasting responses to LPS indicate that TNFα and IL-1 regulate different processes. A large-scale proteomic analysis of TNFα- and IL-1-induced responses was undertaken to identify processes uniquely regulated by TNFα and IL-1. When combined with genomic studies, our results indicate that TNFα, but not IL-1, mediates cell cycle arrest. PMID:17503796

  7. Factor de necrosis tumoral alfa en pacientes con preeclampsia a término y pretérmino

    Directory of Open Access Journals (Sweden)

    Eduardo Reyna Villasmil

    2012-07-01

    necrosis tumoral alfa, preeclampsia, citokinas. Tumor necrosis factor alpha in term and pre-term preeclamptic patients Abstract The objective of research was to know and compare concentrations of tumor necrosis factor alpha in term and pre-term preeclamptic patients. Fifty patients were selected. Twenty pre-term preeclamptic patients (group A and thirty term preeclamptic patients (group B were selected. Blood samples for tumor necrosis factor alpha was collected in all patients before labor and immediately after diagnosis of preeclampsia. There were not significant differences related to a maternal age and body mass index at the moment of collecting samples. There were significant differences between groups in gestational age (p < 0,00001. Mean value of systolic blood pressure in group A was 149.4 ± 11.3 mmHg while in patients of group B was 148.1 ± 12.3 mmHg (p = 0.7071 and mean value od diastolic blood pressure in group A was 103.8 ± 8,6 mmHg and in group B was 102.7 ± 7.9 mmHg (p = 0,6436. Tumor necrosis factor alpha concentrations were similar in study group A (98.2 ± 45.1 pg/mL compared with group B (96.6 ± 48.7 pg/mL; p = 0.9072. When correlation was calculated between values of necrosis tumor factor alpha with values of blood pressure there was observed that there was no correlation with systolic blood pressure (r = 0.129; p = 0.374 nor diastolic blood pressure (r = 0.158; p = 0.273. It is concluded that blood concentrations of tumor necrosis factor alfa were similar in preeclamptic patients wit pre-term and term pregnacy. Correlation of tumor necrosis factor alfa with values of systolic and diastolic blood pressure were not significant.

  8. Modulation of tumor necrosis factor by microbial pathogens.

    Directory of Open Access Journals (Sweden)

    2006-02-01

    Full Text Available In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcome or deflect the host responses mediated by TNF. For example, modulatory proteins encoded by multiple families of viruses can block TNF and TNF-mediated responses at multiple levels, such as the inhibition of the TNF ligand or its receptors, or by modulating key transduction molecules of the TNF signaling pathway. Bacteria, on the other hand, tend to modify TNF-mediated responses specifically by regulating components of the TNF signaling pathway. Investigation of these diverse strategies employed by viral and bacterial pathogens has significantly advanced our understanding of both host TNF responses and microbial pathogenesis. This review summarizes the diverse microbial strategies to regulate TNF and how such insights into TNF modulation could benefit the treatment of inflammatory or autoimmune diseases.

  9. Membrane Tumor Necrosis Factor Confers Partial Protection to Listeria Infection

    Science.gov (United States)

    Torres, David; Janot, Laure; Quesniaux, Valerie F.J.; Grivennikov, Sergei I.; Maillet, Isabelle; Sedgwick, Jonathon D.; Ryffel, Bernhard; Erard, Francois

    2005-01-01

    Tumor necrosis factor (TNF) plays a critical role in the host response to the intracellular pathogen Listeria monocytogenes (LM). TNF exists in soluble and membrane-bound forms and exhibits both unique and overlapping activities. We examined the role of membrane TNF in the absence of secreted TNF for host resistance in knockin mice in which the endogenous TNF was replaced by a regulated, noncleavable allele (mem-TNF). Macrophages expressing mem-TNF produced nitric oxide and displayed normal bactericidal activity. Although mice completely deficient in TNF (TNF−/−) succumbed to LM infection within 4 days, mem-TNF mice controlled LM infection at a low dose (104 CFU) but succumbed at a higher dose of infection (105 CFU). In contrast to complete TNF deficiency, mem-TNF mice developed confined microabscesses that expressed inducible nitric oxide synthase. The transfer of lymphocytes from immunized mem-TNF, but not TNF−/−, mice protected TNF−/− mice from fatal infection. Taken together the data suggest that in the absence of soluble TNF, the presence of membrane-expressed TNF on phagocytes and lymphocytes partially restores host defense to LM infection. PMID:16314479

  10. ROLE OF TUMOR NECROSIS FACTOR IN NEONATAL SEPSIS

    Institute of Scientific and Technical Information of China (English)

    史源; 沈际臬; 汪江淮; 李华强; 覃世文; 刘韧

    1994-01-01

    In order to assess the role of tumor necrosis factor (TNF) in neonatal sepsis,plasma TNF levels were deter-mined by a method using L929 cells at the time of septic work-up in 67 neonates.Thirty-three patients with sepsis were found to have significantly higher TNF levels (533.33±468.74U/ml;1U corresponding to 1.67 pg re-combinant TNF)as compared with 34 non-sepsis patients (100.0±188,974U/ml)and 30 healthy newborns (27.33±16.17U/ml,P<0.05,respectively),The upper limit of normal plasma TNF levels was 60U/ml and the best cutoff value for predicting neonatal sepsis was 160U/ml.This had remarkable sensitivity (88%).Plasma TNF levels were significantly associated with the occurrence of shock,organ failure,sclerema and outcome.Thus,anti-TNF anti-bodies might be used in protecting newborns from septic death.

  11. Persistence of interleukin 7 activity and levels on tumour necrosis factor alpha blockade in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    van Roon, Joel A. G.; Hartgring, Sarita A. Y.; Wijk, Marion Wenting-van; Jacobs, Kim M. G.; Tak, Paul-Peter; Bijlsma, Johannes W. J.; Lafeber, Floris P. J. G.

    2007-01-01

    Objectives: To identify the mechanism of interleukin (IL)7-stimulated tumour necrosis factor alpha (TNF alpha) production and to determine the relationship between intra-articular IL7 and TNF alpha expression levels in patients with rheumatoid arthritis ( RA). In addition, the effect of TNF alpha bl

  12. Granulomatous salmonella osteomyelitis associated with anti-tumor necrosis factor therapy in a non-sickle cell patient: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Gould, Elaine S.; Gilet, Anthony G. [State University of New York at Stony Brook, Department of Radiology, Stony Brook, NY (United States); Vigorita, Vincent J. [SUNY Health Sciences Center Brooklyn, Department of Pathology and Orthopedics, Brooklyn, NY (United States)

    2010-08-15

    Salmonella osteomyelitis is seen most commonly in patients with sickle cell disease and in those with compromised immune systems. We report on the clinical, histological and imaging findings of salmonella osteomyelitis with intraosseous abscess formation occurring in a non-sickle cell patient receiving anti-tumor necrosis factor (TNF) alpha therapy. (orig.)

  13. Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression.

    NARCIS (Netherlands)

    Netea, M.G.; Radstake, T.R.D.J.; Joosten, L.A.B.; Meer, J.W.M. van der; Barrera Rico, P.; Kullberg, B.J.

    2003-01-01

    OBJECTIVE: Patients treated with antibodies to tumor necrosis factor alpha (TNFalpha) have an increased susceptibility to intracellular infections. We describe 2 patients with rheumatoid arthritis (RA) who developed Salmonella septicemia during anti-TNF treatment. The aim of this study was to identi

  14. Tumor necrosis factor- α infliximab inhibits osteoclast formation of peripheral blood mononuclear cells but does not affect periodontal ligament fibroblast-mediated osteoclast formation

    NARCIS (Netherlands)

    de Vries, T.J.; Yousovich, J.; Schoenmaker, T.; Scheres, N.; Everts, V.

    2016-01-01

    Background and Objective: The inflammatory cytokine tumor necrosis factor-alpha (TNF-α) is elevated in inflamed periodontal tissues and may contribute to periodontitis progression. TNF-α stimulates formation and activity of osteoclasts, the cells that are recruited in periodontitis, that cause alveo

  15. Purification of human immunoglobulin G autoantibodies to tumor necrosis factor using affinity chromatography and magnetic separation.

    Science.gov (United States)

    Sennikov, S V; Golikova, E A; Kireev, F D; Lopatnikova, J A

    2013-04-30

    Autoantibodies to cytokines are important biological effector molecules that can regulate cytokine activities. The aim of the study was to develop a protocol to purify autoantibodies to tumor necrosis factor from human serum, for use as a calibration material to determine the absolute content of autoantibodies to tumor necrosis factor by enzyme-linked immunosorbent assay. The proposed protocol includes a set of affinity chromatography methods, namely, Bio-Gel P6DG sorbent to remove albumin from serum, Protein G Sepharose 4 Fast Flow to obtain a total immunoglobulin G fraction of serum immunoglobulins, and Affi-Gel 15 to obtain specifically antibodies to tumor necrosis factor. The addition of a magnetic separation procedure to the protocol eliminated contaminant tumor necrosis factor from the fraction of autoantibodies to tumor necrosis factor. The protocol generated a pure fraction of autoantibodies to tumor necrosis factor, and enabled us to determine the absolute concentrations of different subclasses of immunoglobulin G autoantibodies to tumor necrosis factor in apparently healthy donors.

  16. Percentage tumor necrosis following chemotherapy in neuroblastoma correlates with MYCN status but not survival.

    Science.gov (United States)

    Bomken, Simon; Davies, Beverley; Chong, Leeai; Cole, Michael; Wood, Katrina M; McDermott, Michael; Tweddle, Deborah A

    2011-03-01

    The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma.

  17. Infections and treatment of patients with rheumatic diseasesTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Atzeni, F.; Bendtzen, K.; Bobbio-Pallavicini, F.;

    2008-01-01

    Glucocorticoids (GCs) have many complex quantitative and qualitative immunosuppressive effects which induce cellular immunodeficiency and increase host susceptibility to various viral, bacterial, fungal and parasitic infections. As cortisol secretion is inadequate in chronic immune/inflammatory c...... lupus erythematosus (SLE) or RA. These vaccinations are generally immunogenic (i.e., capable of inducing a protective level of specific antibodies) but may not induce an adequate response in a substantial proportion of patients Udgivelsesdato: 2008/1......, and for the shortest possible time should therefore greatly reduce the risk of infections. Infection is a major co-morbidity in rheumatoid arthritis (RA), and conventional disease-modifying anti-rheumatic drugs (DMARDs) can increase the risk of their occurrence, including tuberculosis. TNF-alpha plays a key role...... in the pathogenesis of RA, and the data concerning infections in RA patients treated with anti-TNF agents are controversial. Patients and physicians should vigilantly monitor for signs of infection when using anti-TNF agents. Recombinant gene technologies now make it possible to produce protein drugs that are almost...

  18. Effects of serum on tumor necrosis factor alpha induced chondrocyte apoptosis following electro-acupuncture%电针后血清对肿瘤坏死因子α诱导软骨细胞凋亡的影响

    Institute of Scientific and Technical Information of China (English)

    吴明霞; 李西海; 吴广文; 李俐; 陈文列; 刘献祥

    2011-01-01

    BACKGROUND: Electro-acupuncture (EA) can promote blood circulation, remove blood stasis, regulate vital energy circulation to relieve pain, relieve rigidity of muscles and actuate collaterals, and effectwely relieve symptoms of osteoarthritis. OBJECTIVE: To observe the effect of serum ontumor necrosis factor a (TNF-a) induced chontroclye apoptosE following EA METHODS: Knee joint chondrocytes from3-week-old SD rats were isolated using enzymatic digestion and apoptosE induced with 10 ug/L TNF-a m vitro. The normal group rats were routine^ rased and did not recede any treatment. The osteoarthritis rats were routinely rased, intraarticularly injected with sodium hyaluronate(p.4uUg. Once a week, fo r s u ccess we 5 weeks), or gwen EA at the Ateixiyan and Wakiyan (5. 15 and 30 min/d). And all rats were interfered with serum, and then the apoptotic rate of theRESULT SAND CONCLUSION: After 15 and 30 minutes of EA at the Afekiyan and Wakiyan, osteoarthrfe rafe we re interfere d with serum for 24 hours. The activrty of chondrocytes was significantly increased and the apoptotic rate of the chondroytes was significantly decreased. These findings suggest that serum can inhibit TNF-a induced chondrocyte apoptosis following EA%背景:电针具有活血化瘀、行气止痛、舒筋通络的作用,能有效缓解骨性关节炎的临床症状.目的:观察电针后血清对肿瘤坏死因子α 诱导软骨细胞凋亡的影响.方法:采用机械-酶消化法分离3 周龄SD大鼠膝关节软骨细胞,用10 μg/L 的肿瘤坏死因子α 诱导体外培养软骨细胞的凋亡,同时给予正常大鼠血清、骨性关节炎大鼠血清、透明质酸钠治疗的骨性关节炎大鼠血清、及电针内、外膝眼5,15,30 min 治疗的骨性关节炎大鼠血清进行干预.结果与结论:电针内、外膝眼15,30 min 治疗的骨性关节炎大鼠血清干预24 h,软骨细胞活力显著增高,凋亡显著减少.说明电针后血清能有效抑制肿瘤坏死因子α 诱导的软骨细胞凋亡.

  19. Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum.

    Science.gov (United States)

    Kennedy, Catherine L; Smith, Danielle J; Lyras, Dena; Chakravorty, Anjana; Rood, Julian I

    2009-07-01

    Programmed necrosis is a mechanism of cell death that has been described for neuronal excitotoxicity and ischemia/reperfusion injury, but has not been extensively studied in the context of exposure to bacterial exotoxins. The alpha-toxin of Clostridium septicum is a beta-barrel pore-forming toxin and a potent cytotoxin; however, the mechanism by which it induces cell death has not been elucidated in detail. We report that alpha-toxin formed Ca(2+)-permeable pores in murine myoblast cells, leading to an increase in intracellular Ca(2+) levels. This Ca(2+) influx did not induce apoptosis, as has been described for other small pore-forming toxins, but a cascade of events consistent with programmed necrosis. Ca(2+) influx was associated with calpain activation and release of cathepsins from lysosomes. We also observed deregulation of mitochondrial activity, leading to increased ROS levels, and dramatically reduced levels of ATP. Finally, the immunostimulatory histone binding protein HMGB1 was found to be released from the nuclei of alpha-toxin-treated cells. Collectively, these data show that alpha-toxin initiates a multifaceted necrotic cell death response that is consistent with its essential role in C. septicum-mediated myonecrosis and sepsis. We postulate that cellular intoxication with pore-forming toxins may be a major mechanism by which programmed necrosis is induced.

  20. Pre-clinical Evaluation of a Cyanine-Based SPECT Probe for Multimodal Tumor Necrosis Imaging

    NARCIS (Netherlands)

    M.A. Stammes (Marieke A.); Knol-Blankevoort, V.T. (Vicky T.); Cruz, L.J. (Luis J.); Feitsma, H.R.I.J. (Hans R. I. J.); L. Mezzanotte (Laura); Cordfunke, R.A. (Robert A.); Sinisi, R. (Riccardo); Dubikovskaya, E.A. (Elena A.); Maeda, A. (Azusa); DaCosta, R.S. (Ralph S.); Bierau, K. (Katja); Chan, A. (Alan); E.L. Kaijzel (Eric); T.J.A. Snoeks (thomas); E.R. van Beek (Ermond); C.W.G.M. Löwik (Clemens)

    2016-01-01

    textabstractPurpose: Recently we showed that a number of carboxylated near-infrared fluorescent (NIRF) cyanine dyes possess strong necrosis avid properties in vitro as well as in different mouse models of spontaneous and therapy-induced tumor necrosis, indicating their potential use for cancer diagn

  1. Tumor necrosis factor receptors support murine hematopoietic progenitor function in the early stages of engraftment.

    Science.gov (United States)

    Pearl-Yafe, Michal; Mizrahi, Keren; Stein, Jerry; Yolcu, Esma S; Kaplan, Ofer; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2010-07-01

    Tumor necrosis factor (TNF) family receptors/ligands are important participants in hematopoietic homeostasis, in particular as essential negative expansion regulators of differentiated clones. As a prominent injury cytokine, TNF-alpha has been traditionally considered to suppress donor hematopoietic stem and progenitor cell function after transplantation. We monitored the involvement of TNF receptors (TNF-R) 1 and 2 in murine hematopoietic cell engraftment and their inter-relationship with Fas. Transplantation of lineage-negative (lin(-)) bone marrow cells (BMC) from TNF receptor-deficient mice into wild-type recipients showed defective early engraftment and loss of durable hematopoietic contribution upon recovery of host hematopoiesis. Consistently, cells deficient in TNF receptors had reduced competitive capacity as compared to wild-type progenitors. The TNF receptors were acutely upregulated in bone marrow (BM)-homed donor cells (wild-type) early after transplantation, being expressed in 60%-75% of the donor cells after 6 days. Both TNF receptors were detected in fast cycling, early differentiating progenitors, and were ubiquitously expressed in the most primitive progenitors with long-term reconstituting potential (lin(-)c-kit(+) stem cell antigen (SCA)-1(+)). BM-homed donor cells were insensitive to apoptosis induced by TNF-alpha and Fas-ligand and their combination, despite reciprocal inductive cross talk between the TNF and Fas receptors. The engraftment supporting effect of TNF-alpha is attributed to stimulation of progenitors through TNF-R1, which involves activation of the caspase cascade. This stimulatory effect was not observed for TNF-R2, and this receptor did not assume redundant stimulatory function in TNFR1-deficient cells. It is concluded that TNF-alpha plays a tropic role early after transplantation, which is essential to successful progenitor engraftment.

  2. Acurácia diagnóstica do leucograma, proteína C-reativa, interleucina-6 e fator de necrose tumoral-alfa na sepse neonatal tardia Accuracy of white blood cell count, C-reactive protein, interleukin-6 and tumor necrosis factor alpha for diagnosing late neonatal sepsis

    Directory of Open Access Journals (Sweden)

    Jamil P. S. Caldas

    2008-12-01

    Full Text Available OBJETIVO: Avaliar o valor do leucograma, proteína C-reativa (PCR, interleucina-6 (IL-6 e do fator de necrose tumoral-alfa (TNF-α, isoladamente e em conjunto, na detecção da sepse neonatal tardia. MÉTODOS: Estudo de validação diagnóstica. A PCR, IL-6 e TNF-α foram dosados por quimioluminescência à suspeita clínica, 24 e 48 horas depois, e o leucograma unicamente à suspeita. De acordo com evolução clínica e resultados de culturas, três grupos foram definidos: sepse comprovada (SC, sepse provável (SP e não infectados (NI. Os testes estatísticos utilizados foram os de Wilcoxon, qui-quadrado e análise de variância de Friedman e os limites de corte foram obtidos pela construção da curva ROC. RESULTADOS: Estudaram-se 82 crianças, sendo 42 no grupo SC, 16 no SP e 24 NI. Nos três momentos, as medianas da PCR e da IL-6 mostraram-se significativamente mais elevadas nos grupos SC e SP, e as do TNF-α alteraram-se apenas no grupo SC. Os índices diagnósticos da PCR foram elevados nos três momentos e com acurácia superior a do leucograma e semelhante a da IL-6 e a do TNF-α em suas primeiras medidas. Entre as citocinas, não houve diferença estatística entre elas, nem em relação ao leucograma. A associação dos testes não aumentou a capacidade diagnóstica, exceto na combinação entre leucograma e PCR2 e na dosagem seriada de PCR. CONCLUSÕES: A PCR e o leucograma mostram-se úteis no diagnóstico de sepse neonatal tardia e comparáveis à IL-6 e ao TNF-α. A acurácia aumentou com a associação PCR-leucograma e a dosagem seriada da PCR.OBJECTIVE: To evaluate the diagnostic value for late neonatal sepsis of white blood cell count (WBC and assays for C-reactive protein (CRP, interleukin-6 (IL-6 and tumor necrosis factor alpha (TNF-α, in isolation and in conjunction. METHODS: This was a diagnostic test validation study. Chemiluminescence was used to assay CRP, IL-6 and TNF-α at the time of clinical suspicion and again

  3. Magnesium alloy modified by micro-arc oxidation can influence tumor necrosis factor-alpha and interleukin-6 production in macrophages%微弧氧化镁合金对巨噬细胞肿瘤坏死因子和白细胞介素6的影响

    Institute of Scientific and Technical Information of China (English)

    庄岩; 吴锋; 孟改利; 李晓会

    2013-01-01

      背景:微弧氧化处理可提高镁合金的抗腐蚀性能,延缓其降解速率。目的:观察微弧氧化处理镁合金对小鼠巨噬细胞肿瘤坏死因子α和白细胞介素6的影响。方法:在小鼠RAW264.7细胞中分别加入镁合金浸提液(对照组)、微弧氧化处理镁合金浸提液(实验组)及RPMI-1640(空白对照组),1 h后加入脂多糖,作用24 h后,收集细胞上清液,检测肿瘤坏死因子α和白细胞介素6水平,MTT法测定脂多糖刺激前后的RAW264.7细胞活性。结果与结论:①脂多糖刺激前的RAW264.7细胞活性:对照组>实验组>空白对照组(P均0.05)。③脂多糖刺激后RAW264.7细胞白细胞介素6与肿瘤坏死因子α的表达量:对照组白细胞介素6表达量明显高于实验组和空白对照组(P 0.05)。表明微弧氧化处理镁合金对小鼠巨噬细胞活性无明显影响,同时降低了炎性反应。%BACKGROUND: Micro-arc oxidation treatment can improve the corrosion resistance of the magnesium alloy and delay the degradation rate. OBJECTIVE: To investigate the effects of magnesium alloy with micro-arc oxidation treatment on tumor necrosis factor-alpha and interleukin-6 expression in mouse macrophage RAW264.7 cells. METHODS: Extracts of magnesium alloy, magnesium alloy with micro-arc oxidation treatment or RPMI-1640 medium were added to RAW24.7 cells at 1 hour prior to lipopolysaccharide treatment for 24 hours. Then culture supernatants were col ected for measuring the concentrations of tumor necrosis factor-alpha and interleukin-6, and cel proliferation were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. RESULTS AND CONCLUSION: Lipopolysaccharide could significantly increase RAW264.7 cel viability. However, there was no significant difference in lipopolysaccharide-induced RAW264.7 cel viability among the three groups (P > 0.05). But the cel viability in the blank control group was significantly increased

  4. Effects of Tumor Necrosis Factor-alpha on the Osteogenic Differentiation of Mouse Bone Marrow-derived Mesenchymal Stem Cells%肿瘤坏死因子-α对小鼠骨髓间充质干细胞成骨分化影响研究

    Institute of Scientific and Technical Information of China (English)

    何琳琳; 兰飞; 薛小平

    2011-01-01

    Objective: To investigate the effects of tumor necrosis factor-alpha (TNF-α) on the osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (BM-MSCs). Methods: BM-MSCs were cultured in osteogenic media (OS) with TNF-α using BM-MSCs in OS without TNF-α as a control group.Alkaline phosphatase staining was tested on the 7 days and Alizarin Red S (ARS) staining and quantification were tested on the 21 days. On the 7 days, mRNA were extracted from one set of the cells and Runx2 and Osterix mRNA expression were analysed by real-time RT-PCR , another set of the cells were lysed and Runx2 and Osterix protein expression were analysed by SDS-PAGE. Results: TNF-α inhibits alkaline phosphatase activity. TNF-α inhibits mineralized nodules formation. TNF-α inhibits Runx2 and Osterix mRNA and protein expression.Conclusion: TNF-α inhibition of the osteogenic differentiation of mouse BM-MSCs, in part, is through suppressing Runx2 and Osterix mRNA and protein expression which are the two key transcription factors of osteogenic differentiation.%目的:探讨肿瘤坏死因子-α(Tumor Necrosis Factor alpha,TNF-α)对小鼠骨髓间充质干细胞(Bone Marrow-derived Mesenchymal Stem Cells,BM-MSCs)成骨分化的影响.方法:以在促成骨分化培养基(Osteogenic media,OS)中培养的小鼠BM-MSCs作为对照,用含有TNF-α的OS处理小鼠BM-MSCs.第7天进行碱性磷酸酶染色,或培养第21天进行茜素红染色和定量分析.第7天时用一份细胞提取得到的mRNA通过实时定量RT-PCR测定Runx2和Osterix的mRNA表达,用另一份细胞得到的细胞裂解液通过SDS-PAGE来测定Runx2和Osterix的蛋白质表达.结果:TNF-α抑制碱性磷酸酶活性;TNF-α抑制矿化骨节的形成;TNF-α抑制Runx2和Osterix的mRNA和蛋白质表达.结论:TNF-α对小鼠BM-MSCs成骨分化的抑制,可能部分是通过抑制成骨分化中两个关键的转录因子Runx2和Osterix的mRNA和蛋白质表达来实现的.

  5. Quantification of active infliximab in human serum with liquid chromatography-tandem mass spectrometry using a tumor necrosis factor alpha -based pre-analytical sample purification and a stable isotopic labeled infliximab bio-similar as internal standard: A target-based, sensitive and cost-effective method.

    Science.gov (United States)

    El Amrani, Mohsin; van den Broek, Marcel P H; Göbel, Camiel; van Maarseveen, Erik M

    2016-07-08

    The therapeutic monoclonal antibody Infliximab (IFX) is a widely used drug for the treatment of several inflammatory autoimmune diseases. However, approximately 10% of patients develop anti-infliximab antibodies (ATIs) rendering the treatment ineffective. Early detection of underexposure to unbound IFX would result in a timely switch of therapy which could aid in the treatment of this disease. Streptavidin coated 96 well plates were used to capture biotinylated-tumor necrosis factor -alpha (b-TNF-α), which in turn was used to selectively extract the active form of IFX in human serum. After elution, IFX was digested using trypsin and one signature peptide was selected for subsequent analysis on liquid chromatography-tandem mass spectrometry (LC-MS/MS). The internal standard used was a stable isotopic labeled IFX bio-similar. The assay was successfully validated according to European Medicines Agency (EMA) guidelines and was found to be linear in a range of 0.5-20μg/mL (r(2)=0.994). Lower limit of quantification for the assay (<20% CV) was 0.5μg/mL, requiring only 2μL of sample. Cross-validation against enzyme-linked immunosorbent assay (ELISA) resulted in a high correlation between methods (r(2)=0.95 with a ρc=0.83) and the accuracy was in line with previously published results. In conclusion, a sensitive, robust and cost-effective method was developed for the bio-analysis of IFX with LC-MS/MS by means of a target-based pre-analytical sample purification. Moreover, low volume and costs of consumables per sample promote its feasibility in (pre)clinical studies and in therapeutic drug monitoring. This method should be considered as first choice due to its accuracy and multiple degree of selectivity.

  6. Hydrogen sulfide inhibits tumor necrosis factor alpha induced inflammatory response of keratinocytes via nuclear factor-kappa B pathway%硫化氢通过核因子-kappa B途径抑制肿瘤坏死因子alpha诱导的角质形成细胞的炎症反应

    Institute of Scientific and Technical Information of China (English)

    Ammar K H Ashorafa; 郭庆; 曾凡钦; 陈敏春; 谭国珍; 唐增奇; 尹若菲

    2011-01-01

    目的:探讨外源性硫化氢(Hydrogen sulfide,H2S)对肿瘤坏死因子alpha(Tumor necrosis factor alpha,TNF-α)诱导的角质形成细胞分泌炎症因子白细胞介素6 (Interleukin 6,IL-6)、白细胞介素8(Interleukin 8,IL-8)以及一氧化氮(Nitric oxide,NO)的影响,并探讨核转录因子kappa B(Nuclear factor kappa B,NF-κB)信号通路途径是否参与此过程.方法:应用TNF-α诱导HaCat细胞分泌炎症因子,以硫氢化钠(Sodium hydrosulfide,NaHS)作为H2S的供体,设置不同浓度的量效组.采用ELISA法测定HaCat细胞分泌IL-6和IL-8的水平,RT-PCR法检测HaCat细胞IL-6和IL-8的mRNA水平,Griess法检测HaCat细胞分泌NO水平,Western blot检测HaCat细胞胞内诱导型一氧化氮合酶(Inducible nitric oxide synthase,iNOS)、磷酸化I-kappa B-alpha(Phosphorylation of I-kappa B-alpha,p-IKB-α)和胞核内NF-κB P65水平.结果:10 ng/ml的TNF-α能显著诱导HaCat细胞内IL-6和IL-8因子的转录和分泌,培养上清NO产量和胞内iNOS含量明显增高,胞内p-IKB-α和胞核P65水平明显提高.在TNF-α诱导HaCat细胞前1h,给与20~400 μmol/L的NaHS做预处理,结果显示NaHS呈剂量依赖性地抑制HaCat细胞分泌IL-6、IL-8和NO,并能部分抑制NF-κB信号通路的活化.结论:H2S通过抑制NF-κB信号通路的活化来抑制TNF-α诱导角质形成细胞的炎症反应.%Objective:To investigate the effects of exogenous hydrogen sulfide(H2S) on the production of interleukin 6 (IL-6) ,inter-leukin 8(IL-8) ,and nitric oxide (NO) in keratinocytes induced by tumor necrosis factor alpha (TNF-α) ,and to explore whether nu-clear factor kappa B(NF-κB) signaling pathway is involved in this process. Methods: HaCat cells were induced by TNF-α to secrete inflammatory factors,and the H2S donor,sodium hydro-sulfide (NaHS),was added to the medium with different concentrations.The levels of IL-6 and IL-8 secreted by HaCat cells were measured by ELISA method ;RT-PCR was performed to detect IL-6 and IL-8

  7. Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein.

    OpenAIRE

    Gray, P W; Barrett, K; Chantry, D; Turner, M.; Feldmann, M

    1990-01-01

    The cDNA for one of the receptors for human tumor necrosis factor (TNF) has been isolated. This cDNA encodes a protein of 455 amino acids that is divided into an extracellular domain of 171 residues and a cytoplasmic domain of 221 residues. The extracellular domain has been engineered for expression in mammalian cells, and this recombinant derivative binds TNF alpha with high affinity and inhibits its cytotoxic activity in vitro. The TNF receptor exhibits similarity with a family of cell surf...

  8. A comparison of the intoxication pathways of tumor necrosis factor and diphtheria toxin

    Energy Technology Data Exchange (ETDEWEB)

    Chang, M.P.

    1988-01-01

    The mechanism by which tumor necrosis factor-alpha (TNF) initiates tumor cell destruction is unknown. We have approached this problem by comparing the biological properties of TNF with diphtheria toxin (DTx), a well-characterized cytotoxin. Initial studies with human U937 cells revealed that a transient exposure to low pH enhances the cytotoxic activity of TNF. Detailed studies on the interaction of TNF with pure lipid vesicles revealed that the acid-enhanced cytolytic activity of this cytokine is correlated with the acquisition of membrane binding and insertion properties. Significantly, an increase in target membrane stabilization was observed in the presence of TNF; hence, TNF is not directly lytic for membranes. In susceptible target cells, DTx induces the release of {sup 51}Cr- and {sup 75}Se-labeled proteins within 7 h. Although DTx-triggered cell death has generally been accepted as a straightforward effect of translation inhibition, little or no cell lysis was observed over a 20-30 h period when target cells were exposed to cycloheximide, amino acid deficient medium or metabolic poisons even though protein synthesis was inhibited to levels observed with DTx. The protein synthesis inhibition and cytolytic activities of DTx showed similar dose-dependencies, target cell specificities, and sensitivities to NH{sub 4}Cl inhibition. DTx-induced DNA fragmentation preceded cells lysis and did not occur in cells that were treated with the other protein synthesis inhibitors.

  9. Increase of tumor necrosis factor receptor 1 expression in women with unexplained early spontaneous abortion

    Institute of Scientific and Technical Information of China (English)

    YAN Chun-fang; YU Xue-wen; JIN Hui; LI Xu

    2004-01-01

    To investigate membrane tumor necrosis factor receptor 1 protein expression level in decidua andconcentration of soluble tumor necrosis factor receptor 1 in serum in women with unexplained early spontaneous abortion,threatened abortion, and compare the levels with healthy pregnant women. Methods: Thirty-seven women with unexplainedearly spontaneous abortion, 27 women with threatened abortion, and 34 healthy pregnant women undergoing artificial abortionof pregnancy at 6 - 10 weeks of gestation were selected. Decidual samples were collected when women were undergoing arti-ficial abortion, and blood samples were collected at the same time. The level of membrane tumor necrosis factor receptor 1 indecidua was detected by flow cytometer, and the concentration of soluble tumor necrosis factor receptor 1 in sera was mea-sured with an enzyme-linked immunosorbent assay. Results: The ercentages of membrane tumor necrosis factor receptor 1positive decidual cells were 16.42 ± 7.10 Mean ± SD for women with unexplained early spontaneous abortion and 13.14 ±6.30 for healthy pregnant women ( P < 0.05). Serum oncentration of soluble tumor necrosis factor receptor 1 was signifi-cantly higher in women with unexplained early spontaneous abortion than in healthy pregnant women and in women withthreatened abortion, and no difference was found between healthy pregnant women and women with threatened abortion.Conclusion: Women with unexplained early spontaneous abortion present significantly higher expression of tumor necrosisfactor receptor 1 than healthy pregnant women, suggesting that over-expression of tumor necrosis factor receptor 1 may cont-ribute to the development of early spontaneous abortion.

  10. Implication of Tumor Necrosis Factor - Alpha in Preeclampsia

    Directory of Open Access Journals (Sweden)

    Dan MIHU

    2008-12-01

    Full Text Available Introduction: Preeclampsia is an exacerbation of a generalized inflammatory response, physiologically present in the third trimester of pregnancy.Aim: The aim of the study consists in the evaluation of proinflammatory cytokine TNF-α in the context of preeclampsia. Material and Method: A transversal study was performed in three groups of patients: non-pregnant patients, patients with normal pregnancies in the third trimester, patients with preeclampsia. Serum TNF-α levels were determined using the immunometric sandwich EIA method.Results: The results obtained confirm a significant increase (p<0.01 in circulating TNF-α levels in the last trimester of pregnancy, compared to the non-pregnant status. Significantly increased serum TNF-α concentrations (p<0.001 were also found in pregnant patients with preeclampsia, compared to normotensive pregnant women. Conclusion: This proinflammatory cytokine can be a potential marker of the severity of the preeclamptic syndrome, without being an indicator of the fetal status at birth.

  11. A novel grading system for clear cell renal cell carcinoma incorporating tumor necrosis.

    Science.gov (United States)

    Delahunt, Brett; McKenney, Jesse K; Lohse, Christine M; Leibovich, Bradley C; Thompson, Robert Houston; Boorjian, Stephen A; Cheville, John C

    2013-03-01

    Grading of renal cell carcinoma (RCC) has prognostic significance, and there is recent consensus by the International Society of Urological Pathology (ISUP) that for clear cell and papillary RCC, grading should primarily be based on nucleolar prominence. Microscopic tumor necrosis also predicts outcome independent of tumor grading. This study was undertaken to assess whether the incorporation of microscopic tumor necrosis into the ISUP grading system provides survival information superior to ISUP grading alone. Data on 3017 patients treated surgically for clear cell RCC, 556 for papillary RCC, and 180 for chromophobe RCC were retrieved from the Mayo Clinic Registry. Median follow-up periods were 8.9, 9.7, and 8.5 years, respectively. Four proposed grades were defined: grade 1: ISUP grade 1+ISUP grade 2 without necrosis; grade 2: ISUP grade 2 with necrosis+ISUP grade 3 without necrosis; grade 3: ISUP grade 3 with necrosis+ISUP grade 4 without necrosis; grade 4: ISUP grade 4 with necrosis or sarcomatoid/rhabdoid tumors. There was a significant difference in survival between each of the grades for clear cell RCC, and the concordance index was superior to that of ISUP grading. The proposed grading system also outperformed the ISUP grading system when cases were stratified according to the TNM stage. Similar results were not obtained for papillary RCC or chromophobe RCC. We conclude that grading for clear cell RCC should be based on nucleolar prominence and necrosis, that ISUP grading should be used for papillary RCC, and that chromophobe RCC should not be graded.

  12. Tumor Necrosis Factor-α sebagai Prediktor Terjadinya Anemia pada Ibu Hamil di Wilayah Endemis Malaria

    Directory of Open Access Journals (Sweden)

    Rostika Flora

    2015-04-01

    Full Text Available Ibu hamil yang berada di daerah endemis malaria sangat rentan terhadap infeksi malaria selama kehamilan. Gejala malaria pada kelompok ini sering asimptomatik atau bahkan tidak terdeteksi sama sekali karena adanya efek imunitas protektif melalui infeksi yang berulang. Adanya peningkatan kadar tumor necrosis factor-alpha (TNF-α dapat dijadikan indikator terjadinya infeksi malaria. TNF-α berperan penting dalam respons imun pada malaria akut yang menghambat terjadinya eritropoesis. Penelitian ini bertujuan untuk mengetahui hubungan antara kadar TNF-α dengan kejadian anemia pada ibu hamil didaerah endemik malaria vivax. Penelitian ini menggunakan desain potong lintang, dilakukan pada bulan Januari - Februari 2014 di lima wilayah kerja puskesmas Kota Bengkulu. Sampel penelitian adalah ibu hamil di daerah endemis malaria vivax yang diambil secara accidental sampling. Dilakukan pengambilan darah untuk pemeriksaan mikroskopis malaria, kadar TNF-α dan kadar hemoglobin (Hb. Hasil penelitian menunjukkan seluruh ibu hamil memiliki riwayat pernah terinfeksi malaria vivax, walaupun hasil pemeriksaan slide negatif. Terjadi peningkatan kadar TNF- α dengan rerata 6,90 ± 2,48 pg/mL dan penurunan kadar Hb dengan rerata 9,75 ± 0,88 g%. Uji korelasi Spearman didapatkan korelasi negatif yang kuat (r = -0,734 dan bermakna (nilai p < 0,05 antara Kadar TNF-α dengan kadar Hb. Terdapat hubungan yang bermakna antara kadar TNF-α dengan kejadian anemia. Tumor Necrosis Factor-α as Predictor of Anemia Occurrence among Pregnant Mothers in Malaria-Endemic Areas Pregnant mothers living in malaria - endemic area are very susceptible to malaria infection during pregnancy. Malaria symptoms in this group are often asymptomatic or even not detected at all due to protective immunity effect through repeated infections. Any elevation of tumor necrosis factor-alpha (TNF-α level can be used as indicator of malaria infection. TNF-α takes an important role in immune response on

  13. Influence of tumor necrosis factor α in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    von der Schulenburg, Johann-Matthias

    2005-12-01

    Full Text Available Objective: Rheumatoid arthritis (RA is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor α (TNF-α have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-α. Etanercept is a soluble human TNF-α receptor. The report assesses the efficacy of TNF-α-antagonists to down-regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. Methods: A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. Results: Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and

  14. Influence of tumor necrosis factor α in rheumatoid arthritis

    Science.gov (United States)

    Kulp, Werner; Corzillus, Michael; Greiner, Wolfgang; Pientka, Ludger; Siebert, Uwe; von der Schulenburg, Johann-Matthias; Wasem, Jürgen

    2005-01-01

    Objective Rheumatoid arthritis (RA) is the most prevalent inflammatory rheumatic disorder. It is a chronic and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Conventional treatment is based on unspecific immunosuppressive agents, e.g. Methotrexate, Azathioprin or Gold. However, the longterm outcomes of these approaches have been poor with frequently ongoing inflammatory disease activity, functional decline, and temporary or permanent work disability. More recently, antagonists of the human cytokine Tumor Necrosis Factor α (TNF-α) have been introduced that are potent suppressors of inflammatory processes. Infliximab is a chimeric antibody against TNF-α. Etanercept is a soluble human TNF-α receptor. The report assesses the efficacy of TNF-α-antagonists to down-regulate inflammation, improve functional status and prevent joint damage in RA with particular regard to the following indications: Treatment of severe, refractory and ongoing disease activity despite adequate use of conventional antirheumatic agents; and treatment of early RA before conventional treatment failure has been demonstrated. Methods A systematic review of the literature is been performed using established electronic databases. The literature search is supplemented by a hand search of journals and publications relevant to RA, reviews of websites of national and international rheumatologic expert societies, as well as contacts to manufacturers. A priori defined inclusion and exclusion criteria are used for literature selection. Analysis and evaluation of included publications are based on standardised criteria sets and checklists of the German Scientific Working Group for Technology Assessment in Health Care. Results Health Technology Assessment reports and metaanalyses cannot be identified. A total of 12 clinical trials are analysed, as well as national and international expert recommendations and practice guidelines

  15. Effects of Panax ginseng on Tumor Necrosis Factor-α-Mediated Inflammation: A Mini-Review

    Directory of Open Access Journals (Sweden)

    Davy CW Lee

    2011-03-01

    Full Text Available Panax ginseng is one of the most commonly used Chinese medicines in China, Asia and Western countries. The beneficial effects of ginseng have been attributed to the biological activities of its constituents, the ginsenosides. In this review, we summarize recent publications on the anti-inflammatory effects of ginseng extracts and ginsenosides on cellular responses triggered by different inducers including endotoxin, tumor necrosis factor-alpha (TNF-α, interferon-gamma and other stimuli. Proinflammatory cytokines, chemokines, adhesion molecules and mediators of inflammation including inducible nitric oxide synthase, cyclooxygenase-2 and nitric oxide orchestrate the inflammatory response. Ginseng extracts and ginsenosides including Rb1, Rd, Rg1, Rg3, Rh1, Rh2, Rh3 and Rp1 have been reported to have anti-inflammatory properties in different studies related to inflammation. Ginsenosides inhibit different inducers-activated signaling protein kinases and transcription factor nuclear factor-kappaB leading to decreases in the production of cytokines and mediators of inflammation. The therapeutic potential of ginseng on TNF-α-mediated inflammatory diseases is also discussed. Taken together, this summary provides evidences for the anti-inflammatory effects of ginseng extracts and ginsenosides as well as the underlying mechanisms of their effects on inflammatory diseases.

  16. Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

    Institute of Scientific and Technical Information of China (English)

    Marie C Lin; Nikki P Lee; Ning Zheng; Pai-Hao Yang; Oscar G Wong; Hsiang-Fu Kung; Chee-Kin Hui; John M Luk; George Ka-Kit Lau

    2005-01-01

    AIM: To compare the gene expression profile in a pair of HBV-infected twins.METHODS: The gene expression profile was compared in a pair of HBV-infected twins.RESULTS: The twins displayed different disease outcomes. One acquired natural immunity against HBV,whereas the other became a chronic HBV carrier. Eightyeight and forty-six genes were found to be up- or downregulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RTPCR. However, upon HBV core antigen stimulation,TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins.CONCLUSION: TNF-αIP1 may play a role in the innate immunity against HBV.

  17. Effect of tumor necrosis factor-α inhibitors on ambulatory 24-h blood pressure.

    Science.gov (United States)

    Grossman, Chagai; Bornstein, Gil; Leibowitz, Avshalom; Ben-Zvi, Ilan; Grossman, Ehud

    2017-02-01

    Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used in inflammatory rheumatic diseases (IRD). The risk of cardiovascular disease is elevated in patients with IRD and TNF-α inhibitors reduce this risk. We assessed whether the beneficial effect of TNF-α inhibitors on cardiovascular risk is mediated by blood pressure reduction. We measured blood pressure levels with 24-h ambulatory blood pressure measurements device in patients with IRD before and 3 months after treatment with TNF-α inhibitors. The study population consisted of 15 subjects (6 men; mean age 45.9 ± 14.1 years). Most patients had either rheumatoid arthritis or psoriatic arthritis and adalimumab was the most common TNF-α inhibitor used. Mean 24-h systolic and diastolic blood pressure levels remained the same after treatment (121 ± 12/66 ± 7 before and 123 ± 11/67 ± 10 mm Hg after; p = 0.88 and 0.66, respectively). The study demonstrates that TNF-α inhibitors have no effect on blood pressure levels.

  18. Effect of compound salvia miltiorrhiza injection on the secretion of tumor necrosis factor alpha of human peripheral blood mononuclear cells in vitro%复方丹参注射液对人外周血单个核细胞体外分泌TNF-α的影响

    Institute of Scientific and Technical Information of China (English)

    接力刚; 杜红延; 沈鹰; 黄清春; 孙维峰; 韦嵩

    2009-01-01

    Objective To investigate the possible mechanism of compound salvia miltiorrhiza injection in treating ankylosing spondylitis. Methods Human peripheral blood mononuclear cells (PBMC) derived from vein blood of healthy volunteer were divided into five groups and were respectively treated with normal saline, large dose of compound salvia miltiorrhiza injection, moderate dose salvia miltiorrhiza injection, low dose salvia miltiorrhiza injection and dexamethasone repectively fore for 48 h. The level of tumor necrosis factor alpha (TNF -α) in supernatant were determined by radioim-munity. Results The levels of TNF - α in supernatant from large dose compound salvia miltiorrhiza injection group and dexamethasone group were significantly lower than that from normal saline group ( P < 0. 05 ). The level of TNF - α in supernatant from large dose compound salvia miltiorrhiza injection group was significantly lower than those from moderate dose salvia miltiorrhiza injection group and low dose salvia miltiorrhiza injection group. Conclusion Inhibition of TNF - α secretion from human PBMCs may be one of mechanisms of compound salvia miltiorrhiza injection in treating ankylosing spondylitis.%目的 探讨复方丹参注射液治疗强直性脊柱炎(AS)可能的作用机制.方法 将分离的正常人外周血单个核细胞分成5组,分别给予生理盐水、大剂量复方丹参、中荆量复方丹参、小剂量复方丹参和地塞米松;孵育48 h后,提取细胞培养液上清液,用放免法检测肿瘤坏死因子α的含量.结果 大剂量复方丹参组和地塞米松组细胞培养液的上清液TNF-α含量明显低于生理盐水组(P<0.05),大剂量复方丹参组的TNF-α的含量水平明显低于中、小剂量复方丹参组(P<0.05).结论 抑制人PBMC分泌TNF-α可能是复方丹参注射液治疗AS的途径之一.

  19. Relevancy Between Gene Polymorphism of Tumor Necrosis Factor Alpha-induced Protein 3 and Genetic Susceptibility of Allergic Rhinitis%TNFAIP3基因多态性与变应性鼻炎遗传易感性的关联性研究

    Institute of Scientific and Technical Information of China (English)

    杜雅平; 韩军; 焦晓明; 王晓暄

    2016-01-01

    目的 探究肿瘤坏死因子α诱导蛋白3(tumor necrosis factor alpha-induced protein 3,TNFAIP3)基因多态性与变应性鼻炎(allergic rhinitis,AR)遗传易感性的关联性.方法 收集2014年1月至2015年8月我院200例AR患者和200例正常对照的血标本,进行病例对照研究,分别为病例组和对照组,运用限制性片段长度多态性聚合酶链反应和直接测序的方法对从抗凝血中提取的DNA样本中TNFAIP3基因的4个多态位点(rs5029928,rs9494885,rs610604,rs7753873)进行基因分型.结果 病例组和对照组TNFAIP3基因的4个多态性位点基因分型均符合哈迪温伯格平衡.位点rs9494885的等位基因和基因型频率在病例组和对照组中存在统计学差异.病例组的CACA单体型频率明显低于对照组,且经统计学分析差异具有显著性(x2=39.111,P<0.05),病例组的TCCA单体型频率明显高于对照组,且经统计学分析差异具有显著性(x2=9.412,P<0.05).其余指标比较均无明显差异(P>0.05).结论 变应性鼻炎与肿瘤坏死因子诱导蛋白3基因多态性有明显关联性,且TNFAIP3的rs9494885位点多态性与AR的易感性密切相关.

  20. MRI Brain Tumor Segmentation and Necrosis Detection Using Adaptive Sobolev Snakes

    Science.gov (United States)

    Nakhmani, Arie; Kikinis, Ron; Tannenbaum, Allen

    2014-01-01

    Brain tumor segmentation in brain MRI volumes is used in neurosurgical planning and illness staging. It is important to explore the tumor shape and necrosis regions at different points of time to evaluate the disease progression. We propose an algorithm for semi-automatic tumor segmentation and necrosis detection. Our algorithm consists of three parts: conversion of MRI volume to a probability space based on the on-line learned model, tumor probability density estimation, and adaptive segmentation in the probability space. We use manually selected acceptance and rejection classes on a single MRI slice to learn the background and foreground statistical models. Then, we propagate this model to all MRI slices to compute the most probable regions of the tumor. Anisotropic 3D diffusion is used to estimate the probability density. Finally, the estimated density is segmented by the Sobolev active contour (snake) algorithm to select smoothed regions of the maximum tumor probability. The segmentation approach is robust to noise and not very sensitive to the manual initialization in the volumes tested. Also, it is appropriate for low contrast imagery. The irregular necrosis regions are detected by using the outliers of the probability distribution inside the segmented region. The necrosis regions of small width are removed due to a high probability of noisy measurements. The MRI volume segmentation results obtained by our algorithm are very similar to expert manual segmentation. PMID:25302005

  1. Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor

    OpenAIRE

    Yamada, Yasuhiro; Kirillova, Irina; Peschon, Jacques J.; Fausto, Nelson

    1997-01-01

    The mechanisms that initiate liver regeneration after resection of liver tissue are not known. To determine whether cytokines are involved in the initiation of liver growth, we studied the regeneration of the liver after partial hepatectomy (PH) in mice lacking type I tumor necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely impaired in these animals, and the expected increases in the binding of the NF-κB and STAT3 transcription factors shortly after...

  2. Remission of Behcet's disease with anti-tumor necrosis factor monoclonal antibody therapy: a case report

    Directory of Open Access Journals (Sweden)

    Castagna Irene

    2003-08-01

    Full Text Available Abstract Background Behcet's disease (BD is a chronic relapsing multisystem inflammatory disorder with mucocutaneous, ocular, articular, vascular, gastrointestinal and central nervous system manifestations. Tumor necrosis factor (TNF-alpha is believed to play a pivotal role in BD. Therapeutic blockade of the activity of TNF has been successfully given in a short course of therapy with favorable effects in patients with BD refractory to conventional immunosuppressive drugs. We aimed to find out whether a 12-month treatment with infliximab, a chimeric monoclonal antibody to TNF-alpha, had any beneficial effect in reducing relapses of a patient with long-standing BD refractory to conventional immunosuppressive drugs. Case presentation A 54 year-old-woman with a 35-year history of BD with orogenital ulcerations, arthritis in the right knee and retinal lesions compatible with vasculitis received infliximab, 5 mg/kg by a two-hour intravenous infusion. Symptoms improved within 24 hours and eight days later the genital and oral ulcers healed as well as the arthritis in the right knee subsided. The retinal infiltrates completely resolved within 10 days. The infusions were repeated at weeks 2, 6, 14, 22 and then every 8 weeks. The patient was able to return to her domestic daily life. No exacerbation of the mucocutaneous ocular or arthritic symptoms occurred during the treatment period. Conclusions Previous studies have suggested that infliximab given in a short course of treatment is effective in inducing remission of severe mucocutaneous, gastrointestinal and ocular manifestations of BD. Our patient received a 12-month infliximab treatment showing a favorable effect on remission of BD manifestations. The long-term infliximab treatment appears as a new therapeutic option for patients with active BD who failed to respond to conventional immunosuppressive agents.

  3. Extended postinterventional tumor necrosis-implication for outcome in liver transplant patients with advanced HCC.

    Directory of Open Access Journals (Sweden)

    Arno Kornberg

    Full Text Available BACKGROUND: Locoregional interventional bridging therapy (IBT is an accepted neoadjuvant approach in liver transplant candidates with hepatocellular carcinoma (HCC. However, the prognostic value of IBT in patients with advanced HCC is still undefined. AIM: The aim of this trial was to evaluate the impact of postinterventional tumor necrosis on recurrence-free long-term survival after liver transplantation (LT in patients with HCC, especially focusing on those exceeding the Milan criteria on pretransplant radiographic imaging. PATIENTS AND METHODS: A total of 93 consecutive liver transplant candidates with HCC were included in this trial. In 36 patients, tumors were clinically staged beyond Milan criteria prior LT. Fifty-nine patients underwent IBT by transarterial chemoembolization or radiofrequency ablation pretransplantation. Postinterventional tumor necrosis rate as assessed at liver explant pathology was correlated with outcome post-LT. RESULTS: There was no significant difference in 5-year tumor-free survival rate between the IBT- and the non-IBT subpopulation (78% versus 68%, P=0.25. However, tumor response following IBT (≥ 50% tumor necrosis rate at explant pathology resulted in a significantly better outcome 5 years post-LT (96% than tumor non-response to IBT (<50% tumor necrosis rate at explant pathology; 21%; P<0.001. Five-year recurrence-free survival rate was 80% in Milan Out patients with extended post-IBT tumor necrosis versus 0% in Milan Out patients without tumor response to IBT (P<0.001. None of macromorphological HCC features, but only the absence of increased (18F-fluoro-deoxy-glucose ((18FDG uptake on pretransplant positron emission tomography (PET was identified as independent predictor of postinterventional tumor response (P<0.001. CONCLUSION: Our results implicate that extended postinterventional tumor necrosis promotes recurrence-free long-term survival in patients with HCC beyond standard criteria. Pretransplant PET

  4. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells

    NARCIS (Netherlands)

    Endres, S; Fülle, H J; Sinha, B; Stoll, D; Dinarello, C A; Gerzer, R; Weber, P C

    1991-01-01

    Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-alpha) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide (LPS)-induce

  5. Lipopolysaccharide induces expression of tumour necrosis factor alpha in rat brain : inhibition by methylprednisolone and by rolipram

    NARCIS (Netherlands)

    Buttini, M; Mir, A; Appel, K; Wiederhold, KH; Limonta, S; GebickeHaerter, PJ; Boddeke, HWGM

    1997-01-01

    1 We have investigated the effects of the phosphodiesterase (PDE) type TV inhibitor rolipram and of the glucocorticoid methylprednisolone on the induction of tumour necrosis factor alpha (TNF-alpha) mRNA and protein in brains of rats after peripheral administration of lipopolysaccharide (LPS). 2 Aft

  6. Treatment of fistulating pouchitis with tumour necrosis factor-alpha-inhibitor (infliximab)

    DEFF Research Database (Denmark)

    Semb, S.; Nordgaard-Lassen, I.

    2008-01-01

    The surgical first choice treatment for patients with ulcerative colitis (UC) involves total proctocolectomy with ileal pouch-anal anastomosis (IPAA). Postoperative development of pouch-related fistula is a rare complication, but it is associated with significant morbidity, a high recurrence rate...... and is a major cause of pouch failure. We report the use of infliximab, a monoclonal antibody to tumour necrosis factor-alpha, in three patients who developed pouch-related fistula after undergoing IPAA surgery for UC Udgivelsesdato: 2008/12/8...

  7. Prediction of mutant activity and its application in molecular design of tumor necrosis factor-a

    Institute of Scientific and Technical Information of China (English)

    唐卫东; 奚涛; 王波; 郭冬林; 徐贤秀; 朱德煦

    1997-01-01

    Two models for prediction of the activity and stability of site-directed mutagenesis on tumor necrosis factor-α are established. The models are based on straightforward structural considerations, which do not require the elaboration of site-directed mutagenesis on the protein core and the hydrophobic surface area by analyzing the properties of the mutated amino acid residues. The reliabilities of the models have been tested by analyzing the mutants of tumor necrosis factor-α (TNF-α) whose two leucine residues (L29, L157) were mutated. Based on these models, a TNF-α mutant with high activity was created by molecular design.

  8. Distinct domains of M-T2, the myxoma virus tumor necrosis factor (TNF) receptor homolog, mediate extracellular TNF binding and intracellular apoptosis inhibition.

    OpenAIRE

    Schreiber, M; Sedger, L; McFadden, G

    1997-01-01

    The myxoma virus tumor necrosis factor (TNF) receptor homolog, M-T2, is expressed both as a secreted glycoprotein that inhibits the cytolytic activity of rabbit TNF-alpha and as an endoglycosidase H-sensitive intracellular species that prevents myxoma virus-infected CD4+ T lymphocytes from undergoing apoptosis. To compare the domains of M-T2 mediating extracellular TNF inhibition and intracellular apoptosis inhibition, recombinant myxoma viruses expressing nested C-terminal truncations of M-T...

  9. Asbestos fibres and man made mineral fibres: induction and release of tumour necrosis factor-alpha from rat alveolar macrophages.

    OpenAIRE

    Ljungman, A G; Lindahl, M.; Tagesson, C

    1994-01-01

    OBJECTIVES--Mounting evidence suggests that asbestos fibres can stimulate alveolar macrophages to generate the potent inflammatory and fibrogenic mediator, tumour necrosis factor-alpha (TNF-alpha), and that this may play an important part in the onset and development of airway inflammation and lung fibrosis due to asbestos fibre inhalation. Little is known, however, about the ability of other mineral fibres to initiate formation and release of TNF-alpha by alveolar macrophages. Therefore the ...

  10. [Human single chain antibodies directed to tumor necrosis factor].

    Science.gov (United States)

    Vikhrova, M A; Batanova, T A; Lebedev, L R; Shingarova, L N; Frank, L A; Kirpichnikov, M P; Tikunova, N V

    2011-01-01

    Six unique phage antibodies to human TNF have been selected from a combinatorial library of human single chain fragment variable. ELISA and Western-blotting was used to study selected phage antibodies binding with TNF. The specificity of selected antibodies was determined by binding with interferon alpha and gamma, bovine serum albumin, ovalbumin and ubiquitin. Two antibodies, sA1 and sB3, were converted into a soluble single-chain antibody form and their affinity was 2.5 and 13.7 nM respectively.

  11. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy

    NARCIS (Netherlands)

    Bremer, Edwin

    2013-01-01

    The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective in

  12. Interleukin-10 and soluble tumor necrosis factor receptors in cerebrospinal fluid of children with bacterial meningitis

    NARCIS (Netherlands)

    Kornelisse, R.F.; Savelkoul, H.F.J.; Mulder, P.H.G.; Suur, M.H.; Straaten, van der P.J.C.; Heijden, van der A.J.; Sukhai, R.N.; Hählen, K.; Neijens, H.J.; Groot, de R.

    1996-01-01

    The antiinflammatory mediators interleukin (IL)-10 and soluble tumor necrosis factor (TNF) receptors p55 (sTNFR-55) and sTNFR-75 in cerebrospinal fluid (CSF) from 37 children with bacterial meningitis were studied. CSF concentrations of IL-10, sTNFR-55, and sTNFR-75 and of the proinflammatory cytoki

  13. Study on the association between tumor necrosis factor α gene polymorphism and systemic lupus erythematosus.

    Institute of Scientific and Technical Information of China (English)

    王敏

    1999-01-01

    Objective: To examine whether polymorphism within the tumor necrosis factor α(TNFα) gene is associated with the susceptibility and clinic manifestations to systemic lupus erythe matosus (SLE) in the patients of Han ethnic group collected from the Northern China. Methods: TNF1 and TNF2 subtypes

  14. Association of tumor necrosis factor polymorphisms with susceptibility to ulcerative colitis in Chinese Han population

    Institute of Scientific and Technical Information of China (English)

    曹倩

    2006-01-01

    Objective To investigate the association between tumor necrosis factor(TNF) promoter polymorphisms and susceptibility to ulcerative colitis (UC) in the Chinese Han population. Methods Blood samples from 110 unrelated UC patients and 292 healthy controls from Zhejiang Province, Eastern China were studied. Genotyping for 6 common TNF promoter polymorphisms (TNF-

  15. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor

    DEFF Research Database (Denmark)

    Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Babcock, Alicia Anne;

    2009-01-01

    Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infa...

  16. Nonselective matrix metalloproteinase but not tumor necrosis factor-a inhibition effectively preserves the early critical colon anastomotic integrity

    DEFF Research Database (Denmark)

    Ågren, Magnus S.; Andersen, Thomas L.; Andersen, Line;

    2011-01-01

    Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-a (TNF-a) induces MMPs and may influence anastomosis repair.......Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-a (TNF-a) induces MMPs and may influence anastomosis repair....

  17. Tumor necrosis factor induces phosphorylation of a 28-kDa mRNA cap-binding protein in human cervical carcinoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Marino, M.W.; Guidon, P.T. Jr.; Donner, D.B. (Cornell Univ. Graduate School of Medical Sciences, New York, NY (USA)); Pfeffer, L.M. (Rockefeller Univ., New York, NY (USA))

    1989-11-01

    Tumor necrosis factor {alpha} (TNF-{alpha}) stimulated the phosphorylation of a 28-kDa protein (p28) in the ME-180 line of human cervical carcinoma cells. The effect of TNF-{alpha} on the phosphorylation state of p28 was rapid (4-fold increase within 15 min) and persistent, remaining above the basal level for at least 2 hr. The specific binding of {sup 125}I-labeled TNF-{alpha} to cell-surface binding sites, the stimulation of p28 phosphorylation by TNF-{alpha}, and the inhibition of cell proliferation by TNF-{alpha} occurred with nearly identical dose-response relationships. Two-dimensional SDS/PAGE resolved p28 into two isoforms having pI values of 6.2 and 6.1. A phosphorylated cap-binding protein was substantially enriched from lysates of control or TNF-{alpha}-treated ME-180 cells by affinity chromatography with 7-methylguanosine 5{prime}-triposphate-Sepharose. The phosphoprotein recovered from this procedure was the substrate for TNF-{alpha}-promoted phosphorylation, p28. Thus, TNF-{alpha} stimulates the phosphorylation of this mRNA cap-binding protein, which may be involved in the transduction of TNF-{alpha}-receptor binding into cellular responses.

  18. Tumor necrosis factor induces phosphorylation of a 28-kDa mRNA cap-binding protein in human cervical carcinoma cells.

    Science.gov (United States)

    Marino, M W; Pfeffer, L M; Guidon, P T; Donner, D B

    1989-11-01

    Tumor necrosis factor alpha (TNF-alpha) stimulated the phosphorylation of a 28-kDa protein (p28) in the ME-180 line of human cervical carcinoma cells. The effect of TNF-alpha on the phosphorylation state of p28 was rapid (4-fold increase within 15 min) and persistent, remaining above the basal level for at least 2 hr. The specific binding of 125I-labeled TNF-alpha to cell-surface binding sites, the stimulation of p28 phosphorylation by TNF-alpha, and the inhibition of cell proliferation by TNF-alpha occurred with nearly identical dose-response relationships. Two-dimensional SDS/PAGE resolved p28 into two isoforms having pI values of 6.2 and 6.1. A phosphorylated cap-binding protein was substantially enriched from lysates of control or TNF-alpha-treated ME-180 cells by affinity chromatography with 7-methylguanosine 5'-triphosphate-Sepharose. The phosphoprotein recovered from this procedure was the substrate for TNF-alpha-promoted phosphorylation, p28. Thus, TNF-alpha stimulates the phosphorylation of this mRNA cap-binding protein, which may be involved in the transduction of TNF-alpha-receptor binding into cellular responses.

  19. 儿童睡眠呼吸暂停与血浆血管内皮生长因子和肿瘤坏死因子α的相关性研究%Relationship between plasma vascular endothelial growth factor and tumor necrosis factor-alpha and obstructive sleep apnea hypopnea syndrome in children

    Institute of Scientific and Technical Information of China (English)

    李健; 李闯; 柴丽萍; 龚未池

    2014-01-01

    Objective To investigate the relation of plasma vascular endothelial growth factor (VEGF) and tumor necrosis factor-α(TNF-α) with obstructive sleep apnea-hypopnea syndrome(OSAHS) in children.Methods Eighty children were recruited from October 2008 to March 2009,including 60 children with snoring and 20 healthy children without snoring as control.Plasma VEGF or TNF-α concentration was measured by enzyme-linked immunosorbent assay (ELISA) respectively.Sixty children with snoring underwent an overnight polysomnography test their PSG data,including whole night mean saturation (MSaO2),lowest oxygen saturation (LSaO2),desatuation cumulate time/total sleep time (DCT/TST),oxygen desaturation index 3 (ODI3),apnea-hypopnea index (AHI),obstructive apnea index (OAI),were collected and analysed.SPSS 13.0 software was used to analyze the data.Results The levels of plasma VEGF and TNF-α in children with OSAHS (540.45 pg/ml and 311.94 pg/ml) were higher than those in children with snoring alone (234.45 pg/ml and 97.55 pg/ml) or those in healthy children (259.80 pg/ml and 120.70 pg/ml),with statistically significant differences (HC value:14.176 and 15.571,P < 0.05,respectively),but with no statistical difference between children with snoring alone and healthy children (P > 0.05).The differences in plasma VEGF or TNF-α levels between children with moderate and severe hypoxemia and children with mild hypoxemia were not statistically significant (P > 0.05).Spearman rank correlation analysis showed no significant correlation between plasma level of VEGF or TNF-α and LSaO2,MSaO2,ODI3,DCT/TST,OAI,AHI or BMI (r values were <0.5,P>O.05).Conclusion Plasma levels of VEGF and TNF-α increase in children with OSAHS.%目的 了解血浆血管内皮生长因子(vascular endothelial growth factor,VEGF)和肿瘤坏死因子α(tumor necrosis factor-alpha,TNF-α)在儿童阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患儿体内的变化,探讨OSAHS患儿血浆VEGF和TNF-α水

  20. Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor.

    OpenAIRE

    Lantz, M.; Gullberg, U; Nilsson, E; OLSSON, I.

    1990-01-01

    Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammatory responses. A cysteine-rich, highly glycosylated 30-kD TNF-binding protein (TNF-BP) purified from urine may have a role in regulation because it protects in vitro against the biological effects of TNF. The cytotoxic effect of TNF on the fibrosarcoma cell line WEHI 164 was inhibited by 50% at a 10-fold excess of TNF-BP. The binding of TNF to the receptor was partially reversed after the addition of TNF-BP. Results from biosyn...

  1. Characterization of golimumab, a human monoclonal antibody specific for human tumor necrosis factor α.

    Science.gov (United States)

    Shealy, David J; Cai, Ann; Staquet, Kim; Baker, Audrey; Lacy, Eilyn R; Johns, Laura; Vafa, Omid; Gunn, George; Tam, Susan; Sague, Sarah; Wang, Dana; Brigham-Burke, Mike; Dalmonte, Paul; Emmell, Eva; Pikounis, Bill; Bugelski, Peter J; Zhou, Honghui; Scallon, Bernard J; Giles-Komar, Jill

    2010-01-01

    We prepared and characterized golimumab (CNTO148), a human IgG1 tumor necrosis factor alpha (TNFα) antagonist monoclonal antibody chosen for clinical development based on its molecular properties. Golimumab was compared with infliximab, adalimumab and etanercept for affinity and in vitro TNFα neutralization. The affinity of golimumab for soluble human TNFα, as determined by surface plasmon resonance, was similar to that of etanercept (18 pM versus 11 pM), greater than that of infliximab (44 pM) and significantly greater than that of adalimumab (127 pM, p=0.018).  The concentration of golimumab necessary to neutralize TNFα-induced E-selectin expression on human endothelial cells by 50% was significantly less than those for infliximab (3.2 fold; p=0.017) and adalimumab (3.3-fold; p=0.008) and comparable to that for etanercept. The conformational stability of golimumab was greater than that of infliximab (primary melting temperature [Tm] 74.8 °C vs. 69.5 °C) as assessed by differential scanning calorimetry.  In addition, golimumab showed minimal aggregation over the intended shelf life when formulated as a high concentration liquid product (100 mg/mL) for subcutaneous administration.  In vivo, golimumab at doses of 1 and 10 mg/kg significantly delayed disease progression in a mouse model of human TNFα-induced arthritis when compared with untreated mice, while infliximab was effective only at 10 mg/kg. Golimumab also significantly reduced histological scores for arthritis severity and cartilage damage, as well as serum levels of pro-inflammatory cytokines and chemokines associated with arthritis. Thus, we have demonstrated that golimumab is a highly stable human monoclonal antibody with high affinity and capacity to neutralize human TNFα in vitro and in vivo.

  2. Role of tumor necrosis factor-α -308 G/A promoter polymorphism in gastric cancer

    Directory of Open Access Journals (Sweden)

    Amar C Bhayal

    2013-01-01

    Full Text Available Background/Aim: Gastric cancer (GC is the fourth most common cancer and the second most common cause of cancer death world-wide after lung cancer. It is a multifactorial disease with the involvement of both genetic and environmental risk factors. Genetic variation in genes encoding cytokines and their receptors, determine the intensity of the inflammatory response, which may contribute to individual differences in severity of outcome of the disease. Tumor necrosis factor alpha (TNF-α is a potent pro-inflammatory cytokine and acid inhibitor. A bi allelic G to A polymorphism at -308 upstream from the transcription initiation site of the promoter is associated with elevated TNF levels. The present study is aimed at evaluating the role of TNF-α-308 (G → A gene polymorphism and susceptibility to GC. Subjects and Methods: A case-control study was carried out in 114 GC patients and 229 healthy control subjects. TNF-α genotyping at position-308 (G → A was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR method followed by agarose gel electrophoresis. Results: The distribution of TNF-α genotypes at -308 (G → A were GG 28.07%, GA 66.67% and AA 5.26% in GC patients and GG 33.19%, GA 55.89% and AA 10.92% in control subjects. The frequencies of alleles G and A were 0.614 and 0.386 in GC patients and 0.611 and 0.389 in control subjects respectively. Conclusion: The study showed no significant difference in the distribution of genotype and allelic frequencies between GC patients and control subject.

  3. Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

    Directory of Open Access Journals (Sweden)

    Ayesha Fatima

    2015-01-01

    Full Text Available Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ and the Nuclear factor κB (NF-κB component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis.

  4. The effect of transmembrane tumor necrosis factor-alpha on human cervical carcinoma HeLa cells%跨膜型肿瘤坏死因子-α对宫颈癌细胞毒性效应的研究

    Institute of Scientific and Technical Information of China (English)

    蔡晓军; 张林

    2014-01-01

    Objective To study the effect of transmembrane tumor necrosis factor-alpha (TM-TNF-αt) on human cervical carcinoma HeLa cells,and explore the correlations with silencer of death domain (SODD).Methods The expression of proliferating cell nuclear antigen (PCNA) was detected by immunocytochemistry.The expression of SODD in human cervical carcinoma HeLa cells undisposed and after disposed with TM-TNF-α was detected by reverse transcription-polymerase chain reaction,and the influence of TM-TNF-α on human cervical carcinoma HeLa cells was analyzed.Results The positive rate of PCNA in undisposed human cervical carcinoma HeLa cells was 80.3% (155/193),in human cervical carcinoma HeLa cells disposed with TM-TNF-α was 46.7% (85/182),there was statistical difference (P < 0.05).The cycle index of polymerase chain reaction in human cervical carcinoma HeLa cells was 28 times,the amplification product was disposed by 2% agarose gel electrophoresis,the gray scale disposed by TM-TNF-α and undisposed human cervical carcinoma HeLa cells were 1.377 ± 0.170 and 0.815 ± 0.040,there was statistical difference (P < 0.05).Conclusion TM-TNF-α has obvious cytotoxic effect on human cervical carcinoma HeLa cells in vitro which may due to its up-regulating the expression of SODD.%目的 观察跨膜型肿瘤坏死因子-α (TM-TNF-α)对人宫颈癌HeLa细胞的效应,并探讨其与人宫颈癌HeLa细胞死亡结构域沉寂子(SODD)表达的关系.方法 应用免疫细胞化学法检测增殖细胞核抗原(PCNA)表达;应用反转录-聚合酶链反应技术检测未经处理的和经TM-TNF-α作用后的人宫颈癌HeLa细胞SODD的表达情况及TM-TNF-α对其影响.结果 未经处理的人宫颈癌HeLa细胞PCNA阳性率为80.3%(155/193),经TM-TNF-α作用后的人宫颈癌HeLa细胞PCNA阻性率降为46.7%(85/182),两者比较差异有统计学意义(P<0.05).人宫颈癌HeLa细胞的聚合酶链反应循环次数设定为28次,所获扩增产物经2%琼脂

  5. Tumor necrosis factor-alpha influences cbfa1/runx2 gene expression in mouse osteoblasts%肿瘤坏死因子α干预小鼠成骨细胞cbfa1/runx2基因的表达

    Institute of Scientific and Technical Information of China (English)

    朱建华; 张沁; 刘继光

    2011-01-01

    BACKGROUND: Tumor necrosis factor-alpha (TNF-a) can decrease alkaline phosphatase (ALP) activity in periodontal ligamentfibroblasts and inhibit the functional transformation between periodontal ligament fibroblasts and osteoblasts.OBJECTIVE: To investigate the effects of TNF-a on the growth of mouse osteoblasts and cbfa1/runx2 gene expression.METHODS: Well growing mouse osteoblast line MC3T3/E1 were interfered with 20, 40, 60, 80 μg/L TNF-a. The normally culturedcells served as controls. cbfa1/runx2 mRNA expression in osteoblast line MC3T3/E1 was detected by RT-PCR. ALP activity wasdetermined by PNPP method and cell viability was measured by MTT assay.RESULTS AND CONCLUSION: cbfa1/runx2 mRNA expression was observed in the normally cultured osteoblast line MC3T3/E1.With increasing concentration of TNF-a concentration, cbfa1/runx2 mRNA expression, MC3T3/E1 cell viability and ALP activitywere gradually decreased. Results suggested that TNF-a can inhibit osteoblast line MC3T3/E1 growth and cbfa1/runx2 may beinvolved in osteoblast differentiation.%背景:肿瘤坏死因子α可降低牙周膜纤维细胞碱性磷酸酶的活性,抑制牙周膜纤维细胞向成骨细胞的功能转化.目的:观察肿瘤坏死因子α对小鼠成骨细胞生长及cbfa1/runx2基因表达的影响.方法:取生长良好的小鼠成骨细胞系MC3T3/E1细胞,分别以20,40,60,80 μg/L的肿瘤坏死因子α进行干预,以正常培养的细胞作为对照.采用RT-PCR法检测MC3T3/E1细胞cbfa1/runx2 mRNA的表达;PNPP法测定碱性磷酸酶活性;MTT法检测细胞活力.结果与结论:正常培养的MC3T3/E1细胞cbfa1/runx2 mRNA呈阳性表达,随着肿瘤坏死因子α浓度的增高,其表达水平逐渐下降.同时MC3T3/E1细胞活力和碱性磷酸酶活性也随肿瘤坏死因子α浓度的增高而下降.提示肿瘤坏死因子α可抑制MC3T3/E1细胞生长,而cbfa1/runx2可能参与了成骨细胞的分化过程.

  6. Effect of Pioglitazone on Expression of Chemerin,Cmklr1 and Tumor Necrosis Factor-alpha mRNA in Liver of Diabetic Rat Model%吡格列酮对糖尿病大鼠肝脏chemerin、cmklr1及TNF-α mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    李国琪; 于倩; 张捷; 刘德敏

    2012-01-01

    目的:观察噻唑烷二酮类药物对糖尿病大鼠肝脏chemerin、cmklr1及肿瘤坏死因子(TNF)-α mRNA表达的影响.方法:雄性SD大鼠随机分为正常组、糖尿病组与吡格列酮组,尾静脉注射链脲佐菌素制作糖尿病大鼠模型,造模成功后吡格列酮组每天按15 mg/kg经胃灌药,连续给药8周.第8周末处死大鼠留取肝脏组织.采用实时定量PCR法检测大鼠肝脏chemerin、cmklr1及TNF-α mRNA的表达水平.结果:糖尿病组肝脏chemerin表达低于正常组及吡格列酮组,差异均有统计学意义(均P<0.017).3组间肝脏cmklr1表达差异无统计学意义.糖尿病组肝脏TNF-α表达较正常组升高(P<0.017),吡格列酮组较糖尿病组有所降低,但差异无统计学意义.结论:糖尿病大鼠肝脏TNF-α表达增高,吡格列酮可能通过上调chemerin的表达而改善肝脏的胰岛素敏感性.%Objective:To investigate the effect of thiazolidinediones on expression of chemerin, cmklrland tumor necrosis factor (TNF)-alpha mRNA in liver of diabetic rat model. Methods: Male SD rals were randomized into three groups, normal control group, diabetes group and piDglitazone group. Murine diabetic models were induced with streptozotocin (STZ). After successful modeling, pioglitazone [15 mg/(kg·d)] was given to rats of pioglitazone group for 8 weeks. Rats were sacrificed to get liver tissues at the end of 8 weeks. Expressions of chemerin, cmklrl and TNF-α mRXA were detected by the method of real-time quantitative PCR. Results: Results of real-time quantitative PCR showed that expression of chemerin mRNA was significantly lower in diabetes group than that of normal control group and pioglitazone group (P < 0.017). No significant difference was found in expression of cmklrl mRNA between three groups. The expression of TNF-α mRNA was significantly higher in diabetes group than that of normal control group (P < 0.017). Conclusion: The expression of TNF-α mRNA was upregulated in the

  7. The effect of basic periodontal therapy on the tumor necrosis factor-alpha in serum and gingival crevicular fluid in diabetes patients with periodontitis%牙周基础治疗对糖尿病患者血清和龈沟液中肿瘤坏死因子-α的影响

    Institute of Scientific and Technical Information of China (English)

    裴路; 谢晓华; 郭阳; 张瑞敏; 刘枫晨

    2012-01-01

    Objective The aim of this study was to evaluate the effects of basic periodontal therapy on the level of tumor necrosis factor-alpha in serum and gingival crevicular fluid,clinical periodontal measurements,glycemic control in type two diabetic patients (T2DM) with chronic periodontitis.Methods Sixty patients with type two diabetes and chronic periodontitis,randomly divided into basic periodontal therapy group (observation group) and non-basic periodontal therapy group (control group),and each group was 30 patients.All subjects received basic periodontal therapy.Clinical periodontal parameters:probing depth (PD),attachment loss(AL),and plaque index (PLI) were recorded at baseline,1 and 3 months after the treatment,HbA1c and the level of TNF-α in serum and gingival crevicular fluid were measured.Results At 1 and 3 months after treatment,PD,PLI and TNF-α in gingival crevicular fluid significantly reduced (P < 0.05) in observation group,but AL and the concentration of HbAlc and TNF-α in serum reduced significantly 3 months after treatment (P < 0.05),while that of control group had no significant difference after the treatment (P>0.05).Conclusion The basic periodontal therapy can help to control the glucose level,clinical periodontal improvements and decreases TNF-α in serum and gingival crevicular fluid in type two diabetic patients with periodontitis.%目的 观察牙周基础治疗对2型糖尿病伴牙周炎患者血清及龈沟液中肿瘤坏死因子-α(TNF-α)的浓度、临床牙周状态、血糖控制的影响.方法 选取2型糖尿病伴牙周炎患者60例,随机分做牙周基础治疗组(观察组)和不做牙周基础治疗组(对照组),每组各30人.分别在治疗前、治疗后1个月和3个月记录所有患者牙周临床指数:探诊深度(PD),附着丧失(AL)及菌斑指数(PLI),并检测糖化血红蛋白(HbAlc)及血清及龈沟液中TNF-α的含量.结果 观察组中PD、PLI和龈沟液中TNF-α含量在治疗后1个月和3

  8. 黄体酮对活化小胶质细胞TNF-α与IL-1β分泌的影响%Progesterone inhibits the expression of tumor necrosis factor-alpha and interleukin-1β in cultured microglia

    Institute of Scientific and Technical Information of China (English)

    王建平; 王伟; 蒋超

    2009-01-01

    Objective Inflammatory cytokines play important roles in the pathophysiology of cerebral infarction and other central nervous system diseases.This study was designed to investigate the influence of progesterone on lipopolysaccharide-induced expression of tumour necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) in primary cultured microglia.Methods Microglia were obtained from cerebral cortexes of neonatal Sprague Dawley rats.Microglia were separated,purificated, cultured and activated.ELISA was used to detect the level of TNF-α, IL-1β in supernate fluid before and after induced with lipopolysaccharide (LPS) or influenced by progesterone.Results LPS strongly induced the expression of TNF-α, IL-1β in microglia from cerebral cortexes.Progesterone inhibited the expression of TNF-α, IL-1β.Conclusion progesterone significantly reduced the expression of inflammatory factors generated by microglia and inhibited the activation of microglia in vitro.

  9. Human gamma interferon and tumor necrosis factor exert a synergistic blockade on the replication of herpes simplex virus.

    Science.gov (United States)

    Feduchi, E; Alonso, M A; Carrasco, L

    1989-03-01

    The replication of herpes simplex virus type 1 (HSV-1) is not inhibited in either HeLa or HEp-2 cells treated with human alpha interferon (HuIFN-alpha), particularly when high multiplicities of infection are used. However, HuIFN-gamma partially inhibits HSV-1 translation in HEp-2 cells infected at low multiplicities. Under these conditions, the transcription of genes alpha 22, TK, and gamma 0 is greatly diminished. The combined addition of human tumor necrosis factor (TNF) and HuIFN-gamma to HEp-2 cells exerts a synergistic inhibition of HSV-1 translation. Cells treated with both cytokines continue synthesizing cellular proteins, even 20 h after HSV-1 infection. As little as 10 U of IFN-gamma per ml blocked HSV-1 DNA replication, provided that TNF was also present in the medium. Analyses of HSV-1 gene transcription suggest that the action of both TNF and IFN-gamma blocked a step that comes at or prior to early HSV-1 gene expression. This early step in HSV-1 replication inhibited by TNF and IFN-gamma occurs after virus attachment and entry into cells, since the internalization of radioactive HSV-1 virion particles was not blocked by the presence of the two cytokines. Therefore, we conclude that the synergistic action of TNF plus IFN-gamma affects a step in HSV-1 replication that comes after virus entry but before or at the transcription of immediate-early genes.

  10. Naringin Inhibits Tumor Growth And Reduces Interleukin-6 And Tumor Necrosis Factor α Levels In Rats With Walker 256 Carcinosarcoma

    OpenAIRE

    Camargo C.A.; Gomes-Marcondes M.C.C.; Wutzki N.C.; Aoyama H.

    2012-01-01

    The flavonoid naringin is a polyphenolic compound that naturally occurs in citrus. Patients with cancer generally present features of malnutrition and cachexia. Levels of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are raised in patients with cancer. This study was designed to analyze the in vivo effect of naringin in the therapeutic treatment of rats bearing Walker 256 carcinosarcoma (W256). Rats were treated intraperitoneally with different doses o...

  11. Inhibition of tumor necrosis factor-α reduces alveolar septal cell apoptosis in passive smoking rats

    Institute of Scientific and Technical Information of China (English)

    ZHANG Cheng; CAI Shan; CHEN Ping; CHEN Jian-bo; WU Jie; WU Shang-jie; ZHOU Rui

    2008-01-01

    Background Recent studies have revealed that lung cell apoptosis plays an important role in pathogenesis of cigarette-induced chronic obstructive pulmonary disease (COPD).Tumor necrosis factor alpha(TNF-α)is one of the most important cytokines which are involved in COPD.This study aimed at investigating the jnfluence of its inhibitor,recombinant human necrosis factor-alpha receptor Ⅱ:IgG Fc fusion protein(rhTNFR:Fc)on alveolar septal cell apoptosis in passive smoking rats.Methods Forty-eight rats were randomly divided into a normal control group,a passive smoking group,an rhTNFR:Fc intervention group and a sham intervention group.The passive smoking rats were treated by exposure to cigarette smoking daily for 80 days.Afcer smoking for one month the rhTNFR:Fc Intervention group was treated with rhTNFR:Fc by subcutaneous injection,the sham intervention group injected subcutaneousIv with a neutral preparation(normal saline 0.1 ml,manicol 0.8 ml,cane sugar 0.2 mg,Tris 0.024 mg as a control.Lung function was determined and the levels of TNF-α in serum and broncho-alveolar lavage fluid(BALF)were measured with enzyme-linked immunosorbnent assay (ELISA).Lung tissue sections stained by hematoxylin and eosin(HE)were observed for study of morphological alternations.Mean linear intercept(MLI)and mean alveolar numbers(MAN)were measured and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)method was carried out to determine the percentage of positive cells and distribution of apoptotic cells.Results Increased MLI and decreased MAN were found in the passive smoking group compared with both the normal control group and the rhTNFR:Fc intervention group(P<0.05).Forced expiratory volume in 0.3 second(FEV0.3)/forced vital capacity(FVC)and peak expiratory flow(PEF)were lower in the passive smoking group than that in the normal control group(P<0.05).Compared with the sham intervention group,FEV0.3/FVC and PEF increased in the rhTNFR:Fc intervention

  12. Effects of anti-tumour necrosis factor-alpha therapy on the quality of life in Crohn's disease

    NARCIS (Netherlands)

    Van Balkom, BPJ; Schoon, EJ; Stockbrugger, RW; Wolters, FL; Van Hogezand, RA; Van Deventer, SJH; Van Dullemen, HM; Russel, MGVM

    2002-01-01

    Background: Infusion of anti-tumour necrosis factor-alpha appears to be highly effective in patients with Crohn's disease. Aim: To assess the effect of infliximab on the quality of life in patients with active or fistulizing disease, as measured by the inflammatory bowel disease questionnaire, and t

  13. Impact of tobacco smoking on response to tumour necrosis factor-alpha inhibitor treatment in patients with ankylosing spondylitis

    DEFF Research Database (Denmark)

    Glintborg, Bente; Højgaard, Pil; Lund Hetland, Merete;

    2015-01-01

    OBJECTIVES: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care. METHODS: Observational cohort study based on the...

  14. Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery.

    Science.gov (United States)

    Lu, Alex Y; Turban, Jack L; Damisah, Eyiyemisi C; Li, Jie; Alomari, Ahmed K; Eid, Tore; Vortmeyer, Alexander O; Chiang, Veronica L

    2016-11-25

    OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.

  15. Paradoxical Reaction to Golimumab: Tumor Necrosis Factor α Inhibitor Inducing Psoriasis Pustulosa

    Directory of Open Access Journals (Sweden)

    Marien Siqueira Soto Lopes

    2013-11-01

    Full Text Available Importance: Golimumab is a human monoclonal antibody, used for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Adverse reactions are increasing with this class of medication (tumor necrosis factor α inhibitors. Observations: The authors present a case of a female patient who presented with psoriasis pustulosa after the use of golimumab for rheumatoid arthritis. Conclusions and Relevance: Paradoxically, in this case, golimumab, which is used for psoriasis, induced the pustular form of this disease. We are observing an increasing number of patients who develop collateral effects with tumor necrosis factor α inhibitors, and the understanding of the mechanism of action and how these adverse reactions occur may contribute to avoid these sometimes severe situations.

  16. Tumor Necrosis Factor and Lymphotoxin-α Polymorphisms and Severe Malaria in African Populations

    OpenAIRE

    Taane G Clark; Diakite, Mahamadou; Auburn, Sarah; Campino, Susana; Fry, Andrew E.; Green, Angela; Richardson, Anna; Small, Kerrin; Teo, Yik Y; Wilson, Jonathan; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Griffiths, Michael J.; Peshu, Norbert

    2009-01-01

    The tumor necrosis factor gene (TNF) and lymphotoxin-α gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving > 10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF −238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were ...

  17. Endothelial cells undergo morphological, biomechanical, and dynamic changes in response to tumor necrosis factor-α

    OpenAIRE

    Stroka, Kimberly M.; Vaitkus, Janina A.; Aranda-Espinoza, Helim

    2012-01-01

    The immune response triggers a complicated sequence of events, one of which is release of the cytokine tumor necrosis factor-α (TNF-α) from stromal cells such as monocytes and macrophages. In this work we explored the biophysical effects of TNF-α on endothelial cells (ECs), including changes in cell morphology, biomechanics, migration, and cytoskeletal dynamics. We found that TNF-α induces a wide distribution of cell area and aspect ratio, with these properties increasing on average during tr...

  18. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1

    OpenAIRE

    1986-01-01

    Tumor necrosis factor/cachectin (TNF) has been implicated as a mediator of the host response in sepsis and neoplasia. Recent work has shown that TNF can modulate endothelial cell hemostatic properties, suggesting that endothelium is a target tissue for TNF. This led us to examine whether endothelial cells have specific binding sites for TNF and augment the biological response to TNF by elaborating the inflammatory mediator, IL-1. Incubation of 125I-recombinant human TNF with confluent, cultur...

  19. TUMOR NECROSIS FACTOR-α INHIBITORS IN THE TREATMENT OF AXIAL SPONDYLOARTHRITIS, INCLUDING ANKYLOSING SPONDYLITIS

    Directory of Open Access Journals (Sweden)

    S. A. Lapshina

    2016-01-01

    Full Text Available The paper provides guidelines for the use of tumor necrosis factor-α  (TNF-α inhibitors in the treatment of patients with axial spondyloarthritis  (axSpA, including ankylosing spondylitis. It gives data on the efficacy of TNF-α inhibitors in patients with non-radiographic axSpA. By using international and Russian guidelines, the authors lay down indications for this therapy and criteria for evaluation of its efficiency and safety.

  20. INTERLEUKIN-6, INTERLEUKIN-8 AND TUMOR NECROSIS FACTOR-α EXPRESSION IN ULCERATIVE COLITIS

    Institute of Scientific and Technical Information of China (English)

    李琪佳; 宫恩聪; 刘叔平; 鄂文

    2001-01-01

    Objectve To study the new insight into the pathogenesis of ulcerative colitis. Methods Interleukin-6 (IL-6), Interleukin-8 (IL-8) and tumor necrosis factor-α(TNF-α) mRNA expression were assessed in the intestinal mucosa of active (n=32) and inactive (n=18) phase using in situ hybridization. Immunohistochemistry for different leukocyte subsets was performed in biopsy specimens of the intestinal mucosa from 50 patients with ulcerative colitis and 5 healthy controls.

  1. 慢性乙醇中毒患者血清IL-6,TNF-α水平与脑萎缩的相关性%Correlation of brain atrophy with the levels of serum interleukin-6 and tumor necrosis factor alpha in chronic alcoholism patients

    Institute of Scientific and Technical Information of China (English)

    徐平; 吴岳洲; 雷显泽; 张骏; 胡泳涛

    2004-01-01

    BACKGROUND: Alcoholism can lead to wide and serious damages in nervoussystem and could reduce the responses of natural killer cells that can induce thechanges in cell-mediated immunity. However, studies on the relationship be-tween the immune injury in alcoholism and cerebral injury are rare.OBJECTIVE: To discuss the relationship between the changes in the serumlevels of interleukin-6(IL-6) and tumor necrosis factor alpha(TNF-α) andbrain atrophy caused by alcoholism.DESIGN: A case-control study.SETTINGS and PARTICIPANTS: The study was completed in the FirstAffiliated Hospital of Zunyi Medical University. Thirty-two chronic alcoholismpatients were selected from outpatient and inpatient department from Febru-ary 1999 to July 2001, and all of them were males aged from 24 to 64 yearswith an onset age from 24 to 50 years and courses of disease from 2 months to6 years. Thirty healthy males were selected in the control group with an agefrom 30 to 60 years old.INTERVENTIONS: Serum levels of IL-6 and TNF-α were detected by dou-bie-antibody ELISA, which was combined with cranial CT scanning for analysis.MAIN OUTCOME MEASURES: The severity of brain atrophy was deter-mined by the index of ventricle, Huckman value, index of somatic part of lat-eral ventricle and the width of the three ventricles. Corresponding serum IL-6and TNF-α strengths were calculated by standard curve of reagent box.group were(286. 31 ± 104.79) ng/L and(413.34 ±66.87) ng/L respec-tively, which were significantly higher than those of the control group[ (205.43 ± 48.67) ng/L and (261.36 ± 51.48) ng/L respectively] ( P <atrophy patients were(343.75 ±99.59) ng/L and(449.38 ±55.79) ng/Lrespectively, which were significantly higher than those of non - brain atrophypatients[ (228. 88 ± 75.74) ng/L and(337.31 ± 57.96) ng/L respectively]( P < 0. 001 ) . The serum level of TNF-α in chronic alcoholism patientswithout brain atrophy was significantly higher than that of the control groupcorrelated with

  2. Association of tumor necrosis factor-α and -β gene polymorphisms in inflammatory bowel disease

    Science.gov (United States)

    Al-Meghaiseeb, Ebtissam Saleh; Al-Robayan, Abdulrahman A; Al-Otaibi, Mulfi Mubarak; Arfin, Misbahul; Al-Asmari, Abdulrahman K

    2016-01-01

    Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this case–control study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and -β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn’s disease (CD) =95) and 200 age- and sex-matched healthy controls were recruited. TNF-α and TNF-β genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (−308) and -β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (−308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (−308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (−308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population

  3. Serum levels of interleukin-6, tumor necrosis factor-alpha and interferon-gama in infants with and without dengue Níveis séricos de interleucina-6, fator de necrose tumoral-alfa e interferon-gama em crianças menores de um ano com e sem dengue

    Directory of Open Access Journals (Sweden)

    Berta Nelly Restrepo

    2008-02-01

    Full Text Available This study compared the serum levels of IL-6, TNF-alpha and IFN-gamma, in children under 1 year of age with and without dengue. Sera were collected from a total of 41 children living in the Department of Antioquia, Colombia (27 patients with dengue and 14 controls. The results showed higher cytokine levels in children with dengue than without dengue, with statistically significant differences for IL-6 and IFN-gamma. No statistically significant differences were found between clinical forms, although IL-6 and IFN-gamma levels were higher in dengue fever cases than in dengue hemorrhagic fever cases. On the other hand, TNF-alpha levels were higher in dengue hemorrhagic fever than in dengue fever. The levels of IL-6 and TNF-alpha were higher in secondary infection than in primary infection, although IFN-gamma levels were higher in primary infection. These results suggest that IL-6, TNF-alpha and IFN-gamma are involved in dengue infection independently of the clinical form.Este estudo comparou os níveis séricos de IL-6, TNF-alfa e IFN-gama, em crianças menores de um ano com e sem dengue. Os soros foram coletados de um total de 41 crianças residentes no Departamento de Antioquia, Colômbia (27 pacientes com dengue e 14 controles. Os resultados mostraram níveis de citoquinas mais elevadas em crianças com dengue do que naquelas sem dengue, com diferenças estatisticamente significativas para IL-6 and IFN-gama. Não houve diferenças estatisticamente significativas entre formas clínicas, embora os níveis de IL-6 e IFN-gama estivessem mais elevados nos casos de febre do dengue que nos casos de febre hemorrágica do dengue. Por outro lado, os níveis de TNF-alfa estavam mais elevados na febre hemorrágica do dengue que na febre do dengue. Os níveis de IL-6 and TNF-alfa estavam mais elevados em infecções secundárias que em infecções primarias, embora os níveis de IFN-gama estivessem mais elevados em infecções primárias. Estes resultados

  4. Meta-analysis of association of tumor necrosis factor alpha-308 gene promoter polymorphism with gastric cancer%肿瘤坏死因子α-308位点基因多态性与胃癌易感性的Meta分析

    Institute of Scientific and Technical Information of China (English)

    陆培华; 汤韵; 李晨; 沈伟; 纪律; 郭榆江; 陶国清

    2010-01-01

    Objective To assess the association between tumor necrosis factor-alpha(TNF-α)gene promoter region-308 gene polymorphisms and gastric cancer(GC)susceptibility.Methods Published work about TNF-α-308 and GC from PubMed,EMBASE,Cochrane library in English and from Wanfang,CBM in Chinese were searched for relevant articles published by the end of July,2009.Thirty-nine relevant articles were selected and 26 of them met the criteria.The correlated index was extracted for aggregate analysis in RevMan 4.2.Results There were 5225 GC patients and 8473 controls for TNF-α-308 in 26 papers.Overall,allele contrast(G:A and AA:GG)genotype of TNF-α-308 polymorphisms produced significant results in worldwide populations,the OR values were 0.85(95% CI:0.76-0.96 ,P=0.01)and 1.19(95%CI:1.01-1.39,P=0.03).Subgroup analysis showed that OR values of G:A and AA:GG in west population were 0.79(95 % CI:0.70-0.89,P < 0.01)and 1.26(95 % CI:1.04-1.52,P = 0.02),while in east populations subgroup analysis,the OR was 0.97(95% CI:0.75-1.26,P= 0.84).No significant association was observed in non-cardia GC and Helicobacter pylori positive GC,the OR values were 0.90(95% CI:0.79-1.02,P=0.10)and 1.08(95% CI:0.62-1.88,P=0.79).Conclusion TNF-α-308 A allele and AA genotype were associated with a statistically significant increased risk of gastric cancer in western people.%目的 评价肿瘤坏死因子α(TNF-α)基因启动子区-308位点基因多态性与胃癌易感性.方法 检索PubMed、EMBASE数据库、Cochrane图书馆(1966年至2009年7月)及万方、中国生物医学文献数据库(1979年至2009年7月)文献,收集TNF-α-308位点基因多态性与胃癌易感性的病例对照研究,共检索到39篇相关文献,26篇纳入研究.应用RevMan 4.2对各研究结果进行异质性检验和效应值合并.结果 26篇纳入本研究的文献中,共计有5225例胃癌患者和8473例(名)对照人群.总研究人群TNF-α-308位点基因G:A的OR=0.85(95%CI:0.76~0.96,P=0.01),AA

  5. Relationship between the changes of cognitive function and the expression of tumor necrosis factor alpha, interleukin 10 in hippocampus of diabetic rats%糖尿病大鼠海马肿瘤坏死因子α、白细胞介素10表达与认知功能改变的关系

    Institute of Scientific and Technical Information of China (English)

    何婷; 苗雅; 朱奕潼; 李蔚; 钟远

    2014-01-01

    目的 观察糖尿病大鼠认知功能及海马组织肿瘤坏死因子α(TNF-α)、白细胞介素10(IL-10)表达的变化,探讨炎症在糖尿病脑病(DE)发病机制中的作用.方法 30只雄性SD大鼠随机分为对照组和糖尿病组,糖尿病组给予高脂饮食4周后按30 mg/kg注射链脲佐菌素建立2型糖尿病大鼠模型,实验末行水迷宫测试评价两组大鼠认知功能.酶联免疫吸附测定法检测大鼠海马组织的β-淀粉样蛋白(Aβ)的浓度,蛋白质印迹法检测TNF-α和IL-10的表达,免疫组织化学法观察Aβ、TNF-α和IL-10的表达.结果 糖尿病组大鼠在目标象限的探索时间比对照组短[(38.21±3.68)s vs(42.10±2.62)s,t=3.105,P<0.01],原平台穿越次数较对照组也减少[(2.62±0.77)次vs(3.69±0.95)次,t=3.184,P<0.01],糖尿病组Aβ和TNF-α表达较对照组高(均P<0.01),IL-10表达较对照组低(P<0.01),免疫组织化学染色观察糖尿病组Aβ、TNF-α阳性表达明显,IL-10阳性表达较少.结论 糖尿病大鼠认知功能下降,可能与炎症因子表达失衡有关.%Objective To observe changes of cognitive function and the expression of tumor necrosis factor alpha(TNF-α),interleukin 10(IL-10) in hippocampus of diabetic rats,and assess the role of inflammation in the possible pathogenesis of diabetic encephalopathy (DE).Methods 30 male SD rats were randomly divided into control group and diabetes mellitus group.After 4 weeks of feeding high fat diet,diabetes mellitus group according to 30mg/kg injected with streptozotocin to establish type 2 diabetic rat model.At the end of the experiment,cognition were evaluated using water maze test.The concentration of beta-amyloid(Aβ) in hippocampus of diabetic rats were detected through enzyme linked immunosorbent assay,and the expression of TNF-α,IL-10 were detected by Western blotting.The expression of Aβ,TNF-α,IL-10 were observed through immunohistochemistry.Results Time spent in the target quadrant in diabetes

  6. 益气化痰方对慢性阻塞性肺疾病大鼠肺泡灌洗液中AQP5、 TNF-α和MUC5AC的影响%Effect of Yiqi Huatan Decoction on Aquaporin 5, Tumor Necrosis Factor-alpha and MUC5AC in Bronchoalveolar Lavage Fluid of Chronic Obstructive Pulmonary Diseases Rats

    Institute of Scientific and Technical Information of China (English)

    冯立志; 单丽囡; 黄纯美; 陈创荣; 詹少峰; 钟亮环

    2016-01-01

    【目的】观察益气化痰方对慢性阻塞性肺疾病(COPD)大鼠肺泡灌洗液(BALF)水通道蛋白5(AQP5)及其上游信号通道调节因子肿瘤坏死因子-α(TNF-α)和下游信号通道调节因子黏蛋白5AC(MUC5AC)的调节作用。【方法】选用SD大鼠,随机分为空白组,模型组,益气化痰方低、中、高剂量组(剂量分别为7.398、36.99、73.98 g·kg-1·g-1)。除空白组外,其他组均采用香烟熏结合脂多糖气管滴入法复制COPD大鼠模型。采用益气化痰中药煎剂治疗COPD大鼠30 d后取材,观察肺组织苏木精—伊红(HE)染色,采用免疫组织化学法观察AQP5、 TNF-α、 MUC5AC的表达,酶联免疫吸附法(ELISA)测定大鼠肺泡灌洗液(BALF)中AQP5、 TNF-α和MUC5AC的含量。【结果】益气化痰汤各剂量组均可改善COPD大鼠的肺组织病理损害,减弱肺组织MUC5AC、 TNF-α表达,增强AQP5表达。与空白组比较,模型组肺组织BALF中AQP5浓度显著下降(P<0.01), TNF-α和MUC5AC浓度显著升高(P<0.01)。与模型组比较,益气化痰方低、中、高剂量组肺组织BALF中AQP5浓度显著升高(P<0.01), TNF-α和MUC5AC浓度显著下降(P<0.01)。与低、中剂量组比较,益气化痰汤高剂量组作用显著(P<0.01)。【结论】益气化痰方对COPD的疗效可能与水通道转运密切相关。%Objective To investigate Yiqi Huatan Decoction(YHD), a compound recipe with the actions of tonifying Qi and resolving phlegm, on aquaporin 5(AQP5), tumor necrosis factor-alpha(TNF-α)and mucin 5AC(MUC5AC)in bronchoalveolar lavage fluid(BALF)of chronic obstructive pulmonary diseases(COPD)rats. Methods SD rats were randomized into blank control group, model group, and low-, middle- and high-dose YHD groups(in the dosage of 7.398, 36.99, 73.98 g·kg-1·d-1 respectively). The rat model of COPD was induced by cigarette smoking combined with intratracheal

  7. 肿瘤坏死因子-α和转铁蛋白在肺结核感染中的检测及临床意义%Clinical significance of measuring tumor necrosis factor-alpha and transferrin in patients with tuberculosis infection

    Institute of Scientific and Technical Information of China (English)

    王建; 潘洪秋; 孙国华; 龚玉华; 张利莉

    2011-01-01

    目的 通过对肺结核患者肿瘤坏死因子-α(NF-α)和转铁蛋白(TRF)水平的联合测定,探讨它们在肺结核感染中的作用和临床意义.方法 选择547例肺结核患者为病例组,72例健康体检者为对照组.病例组按照结核杆菌涂片结果、临床诊断分型、耐药性差异进行进一步分组,综合分析肺结核患者TNF-α和TRF水平的变化.结果 TNF-α和TRF浓度与痰结核分枝杆菌数量呈正相关;病例组TNF-α水平均高于对照组,差别有统计学意义(P<0.05,P<0.01);TRF水平均高于对照组,除抗酸杆菌阴性者,其余差别均有统计学意义(P<0.01).抗酸杆菌阳性者TNF-α水平均高于抗酸杆菌阴性者,差别有统计学意义(P<0.01);TRF水平抗酸杆菌阳性者均高于抗酸杆菌阴性者,除抗酸杆菌弱阳性者,其余差别均有统计学意义(P<0.01).继发性肺结核和结核性胸膜炎TNF-α水平明显高于原发性肺结核和血行播散性肺结核(P<0.01);血行播散性肺结核TRF水平明显高于原发性肺结核、继发性肺结核及结核性胸膜炎(P<0.01).治疗前,TNF-α和TRF水平在不同耐药者之间差别无统计学意义(P>0.05);治疗后,不同耐药者TNF-α和TRF水平与治疗前比较均下降,除耐多药结核外,其余差别均有统计学意义(P<0.01).结论 TNF-α和TRF的测定对研究结核杆菌致病机制、抗结核治疗疗效观察及耐药性的产生机制具有重要的研究价值.%Objective To simultaneous detect serum concentration of tumor necrosis factor-alpha(TNF-ct) and trans-ferrin(TRF) ,in order to explore their effects and clinical significance in patients with tuberculosis infection. Methods Five hundred and forty-seven cases with pulmonary tuberculosis and 72 cases of healthy individuals were selected as disease group and control group, respectively. The patients in disease group were divided into different groups according to the results of tubercle bacillus smear

  8. 骨髓间充质干细胞移植对急性肝功能衰竭大鼠肝组织miRNA-155和TNF-α表达的影响%Effects of bone marrow mesechymal stem cells on microRNA-155 and tumor necrosis factor alpha expression in liver tissue of rats with acute liver failure

    Institute of Scientific and Technical Information of China (English)

    郑盛; 肖琼怡; 殷芳; 郭致平; 刘汉屈; 王建刚; 朱为梅; 王玉波

    2014-01-01

    Objective To explore the effects of bone mesenchymal stem cells (BMSCs) on the microRNA-155 (miRNA-155) and tumor necrosis factor alpha (TNF-α) expression in liver tissue of rats with acute liver failure (ALF), and to explore the relationship between miRNA-155/TNF-α and the efficacy of BMSCs. Methods SD rats were randomly divided into four groups, including control group, ALF group, BMSC treatment group and BMSC pretreatment group. Rats in each group were sacrificed 7 h after intraperitoneal D-GalN/LPS administration. Liver function, serum TNF-α level, miRNA-155 and TNF-α mRNA of liver tissue were detected subsequently. Survival rate at 24 h was observed in each group. Results Seven hours after D-GalN/LPS induction, alanine aminotransferase and aspartate aminotransferase levels of BMSC treatment and BMSC pretreatment groups were significantly lower when compared with those of ALF group(all P < 0.01). Compared with ALF group, serum levels of TNF-α decreased in BMSC treatment and BMSC pretreatment groups and the difference was statistically significant (all P<0.01). The difference of the TNF-αmRNA expression in liver tissue between groups was statistically significant (F = 72.24, P< 0.01). The TNF-αmRNA and miRNA-155 expression of BMSC treatment and BMSC pretreatment groups were down-regulated in comparison with ALF group, which showed statistical difference (all P<0.01). The positive correlation between miRNA-155 and TNF-αmRNA in liver tissue was confirmed in ALF group (r=0.734, P=0.001), BMSC treatment (r=0.590, P=0.006) and BMSCs pretreatment (r = 0.687, P= 0.004). 24 h after D-GalN/LPS administration, the difference of mortalities between groups was statistically significant (χ2=19.078, P< 0.01). Conclusion With BMSC intervention in ALF, up-regulated miRNA-155 and TNF-αexpressions in liver tissue could be partially reversed by BMSCs, suggesting that BMSC alleciate ALF via regulating miRNA-155 and TNF-α.%目的:探讨骨髓间充质干细胞(BMSCs

  9. Tumour necrosis factor-alpha and interleukin-8 inhibit neutrophil migration in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    F. Q. Cunha

    1992-01-01

    Full Text Available Pretreatment of human neutrophils with recombinant tumour necrosis factor-alpha (rTNF-α and/or interleukin-8 (rIL-8, but not with either transforming growth factor-beta, interleukin-6 or interferon-gamma, rendered these cells less responsive to FMLP, in microchemotaxis assays. This inhibitory effect was dose dependent and more powerful when neutrophils were pretreated with a mixture of both cytokines. Intravenous injection of human rIL-8 (hrIL-8 and/or murine rTNF-α (mrTNF-α also significantly reduced in vivo neutrophil migration into peritoneal cavities of rats stimulated with carrageenan. These data suggest that the defect in neutrophil migration during septicaemia or endotoxaemia may be the result of the continuous release of IL-8 and TNF-α into the circulation. Thus, either the selective control or blockade of releasing of these cytokines as well as of its effects on neutrophils may be clinically useful in reestablishing the cell defence mechanisms.

  10. Plasma histamine and tumour necrosis factor-alpha levels in Crohn's disease and ulcerative colitis at various stages of disease.

    Science.gov (United States)

    Hagel, A F; de Rossi, T; Konturek, P C; Albrecht, H; Walker, S; Hahn, E G; Raithel, M

    2015-08-01

    Mast cells secrete numerous mediators and this study investigated plasma levels of histamine, and tumor necrosis factor alpha (TNF-α) in chronic inflammatory bowel disease (IBD). Plasma levels of histamine were determined in 68 patients with Crohn's disease (CD), 22 with ulcerative colitis (UC) and 13 controls. TNF-α levels were assessed in 29 CD patients, 11 UC patients, and in 11 controls. Plasma histamine levels in the control group were 0.25 ng (0.14 - 0.33) and showed no difference to CD (0.19 ng, 0.09 - 0.35) or UC (0.23 ng, 0.11 - 0.60). Significantly lower histamine levels were only found in CD patients on 5-aminosalicylic acid treatment (P ≤ 0.04). Plasma TNF-α levels in the control group were significantly lower 0.44 ml/m(2) (0 - 1.15) than in CD patients (4.62 ml/m(2), 1.82 - 9.22, P = 0.005) or UC (3.14 ml/m(2); 0.08 - 11.34, P = 0.01). In CD disease activity, fistula, and extraintestinal manifestations (EM) were associated with significantly higher plasma TNF-α values, but not the type of treatment. We concluded that in contrast to TNF-α, histamine levels were normal in CD and UC. There is no correlation with histamine and thus the proportion of TNF-α secreted from mast cells in the plasma in patients with IBD is less important.

  11. Neutrophil Recruitment by Tumor Necrosis Factor from Mast Cells in Immune Complex Peritonitis

    Science.gov (United States)

    Zhang, Yan; Ramos, Bernard F.; Jakschik, Barbara A.

    1992-12-01

    During generalized immune complex-induced inflammation of the peritoneal cavity, two peaks of tumor necrosis factor (TNF) were observed in the peritoneal exudate of normal mice. In mast cell-deficient mice, the first peak was undetected, and the second peak of TNF and neutrophil influx were significantly reduced. Antibody to TNF significantly inhibited neutrophil infiltration in normal but not in mast cell-deficient mice. Mast cell repletion of the latter normalized TNF, neutrophil mobilization, and the effect of the antibody to TNF. Thus, in vivo, mast cells produce the TNF that augments neutrophil emigration.

  12. Fármacos que inhiben el factor de necrosis tumoral α y embarazo

    OpenAIRE

    Cristian Simon, Petru; Vallano Ferraz, Antonio

    2013-01-01

    Pregunta: ?Es segura la administración de los fármacos que inhiben el factor de necrosis tumoral a (TNF-a) durante el embarazo? Respuesta: En los últimos años se han desarrollado medicamentos que inhiben el TNF-a, porque esta citocina tiene un efecto inflamatorio que condiciona el proceso patológico de diversas enfermedades autoinmunitarias sistémicas, como artritis reumatoide, psoriasis, enfermedades inflamatorias intestinales y otras. Actualmente existen en el mercado farmacéutico 5 fármaco...

  13. Tumor Necrosis Factor and the Pathogenesis of Pichinde Virus Infection in Guinea Pigs

    OpenAIRE

    Aronson, Judith F.; Herzog, Norbert K.; Jerrells, Thomas R.

    1995-01-01

    Pichinde virus (PIC) is a reticuloendothelial arenavirus of the New World tropics. A guinea pig passage–adapted strain of this virus (adPIC) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (PIC3739) has attenuated virulence. The abilities of adPIC and PIC3739 to induce tumor necrosis factor (TNF) in vivo and in cultured macrophages were compared. Infection with adPIC, but not PIC3739, was associated with detectable serum TNF that peaked in week 2 of infection. ...

  14. Expression of soluble human tumor necrosis factor receptor Ⅰ in Aspergillus niger

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The cDNA of soluble human tumor necrosis factor receptorⅠ(sTNFRI) was inserted into fusion-protein expression plasmid pIGF of A. niger to construct fusion expression vector pHBC containing a KEX2 like protein processing site designed on the fusion position. Extracellular protease-deficient strain of A. niger 3.795-1-23 was transformed with pHBC. Positive clone was estimated by Southern hybridization. SDS-PAGE for protein produced by re-combinant strain showed the distinctive expression band. Western blotting indicated that the secreted protein had immunoactivity of sTNFRI.

  15. Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors

    OpenAIRE

    1992-01-01

    The receptors for tumor necrosis factor (TNF) exist in cell-associated as well as soluble forms, both binding specifically to TNF. Since the soluble forms of TNF receptors (sTNF-Rs) can compete with the cell- associated TNF receptors for TNF, it was suggested that they function as inhibitors of TNF activity; at high concentrations, the sTNF-Rs indeed inhibit TNF effects. However, we report here that in the presence of low concentrations of the sTNF-Rs, effects of TNF whose induction depend on...

  16. Meta-analysis of association of tumor necrosis factor alpha and transforming growth factor beta gene polymorphisms with Pneumoconiosis%肿瘤坏死因子-α和转化生长因子-β基因多态性与尘肺易感性的Meta分析

    Institute of Scientific and Technical Information of China (English)

    刘乾; 苏文珍; 单永乐; 张志虎; 许光; 张玮; 张海东; 王瑞

    2012-01-01

    Objective To evaluate the relationship between tumor necrosis factor-alpha-238,transforming growth factor beta (509 and 869) gene polymorphisms and pneumoconiosis susceptibility.Methods We searched published full-text from foreign language databases including Elsevier,PubMed,Wiley Online Library,EMCC,Web of Science,chinese databases containing CNKI,VIP,Wanfang,CBM and Cochrane library to collect case-control or cohort study on gene gene polymorphisms said above with pneumoconiosis susceptibility from the year January1988 to August 2011.28 relevant articles were selected and 20 of them met the criteria.The correlated index was extracted for aggregate analysis in RevMan 4.2.Results Among the 20 studies,10 articles on TNF-α238 polymorphism (including 2232 pneumoconiosis cases and 1985 control subjects),4 articles on TGF-β509 polymorphism (including 693 pneumoconiosis cases and 663 control subjects),and 6 articles on TGF-3869 polymorphism (including 1450 pneumoconiosis cases and 1101 control subjects) were included in the current study.Meta-analysis results showed that there was a significant association between TNF-α238 polymorphism and pneumoconiosis:the population with GA and AA genotypes of TNF-α238 had higher risks to pneumoconiosis (OR=1.53,95%CI:1.25~1.88) comparing to GG genotype,and the population with A allele had higher risks to pneumoconiosis comparing to allele G (OR=1.64,95%CI:1.17 ~2.30).The stratified analysis showed that the people with GA and AA genotypes and A allele who were silicosis,Asian or exposed to dust had higher risks to pneumoconiosis (OR=2.14,95%CI:1.20~3.82; OR=2.16,95%CI:1.20~3.88; OR=1.78,95%CI:1.01~3.11; OR=1.83,95%CI:1.04~3.22; OR=1.80,95%CI:1.21~2.66;OR=1.50,95%CI:1.23~1.83).No significant association was found between TGF-β (509 and 869) gene polymorphisms with pneumoconiosis:In contrast to the CC genotype,the population who had CT and TT genotypes had no higher risks to pneumoconiosis( OR=1

  17. 职业慢性心理应激与血清热休克蛋白70及肿瘤坏死因子-α表达水平的关联研究%Association of occupational chronic psychological stress with heat shock protein 70 in serum and tumor necrosis factor-alpha expression levels

    Institute of Scientific and Technical Information of China (English)

    邱方园; 田如龙; 强艳; 贺鹍鹏; 刘贺荣; 张伟; 宋辉

    2016-01-01

    -α的表达水平分别为(133.61±129.51)、(171.23±133.69)、(169.31±196.09) pg/ml(F=6.93,P=0.001).结论 血清HSP70、TNF-α的表达水平受职业慢性心理应激的影响,职业慢性心理应激水平增高时,血清HSP70表达水平降低,TNF-α表达水平升高.%Objective To investigate the relationship between occupational chronic psychological stress with heat shock protein 70 (HSP70) and tumor necrosis factor-alpha (TNF-α).Methods Using case-control study design,we selected 622 cases in 20 to 60 years old and unrelated patients with metabolic syndrome as the case group between October 2011 and October 2012 at two hospitals of Ningxia hui autonomous region.At the same time,we selected 600 healthy people from health check-up crowd in the above two hospitals as control group.The the research objects were sex,age,nation,height,weight,smoking,drinking,exercise,and so on.After informed consent,all the research objects were collected fasting venous blood samples 10 ml in order to proceed laboratory testing of biochemical indicators.The expression of HSP70 and TNF-α in serum was determined by ELISA.Using the revised occupational stress inventory (OSI) to survey the occupational chronic psychological stress factors and stress level of research object.The correlation of occupational chronic psychological stress scores with HSP70 and TNF-α was investigated by partial correlation analysis.We built a multivariate linear regression equation With HSP70 and TNF alpha as the independent variable and occupational chronic psychological stress scores as the dependent variable,using equation of the determination coefficient R2 to judge the degree of fitting equation.Results The total points of chronic stress factors in all respondents was (136.65± 16.19).Among them,the mild stress level group was 313,moderate was 588,severe was 321,chronic heart stress factors scores were (119.96± 13.30),(135.33±3.23),(155.33± 13.55) points,respectively.In the case group

  18. Direct therapeutic applications of calcium electroporation to effectively induce tumor necrosis

    DEFF Research Database (Denmark)

    Frandsen, Stine Krog; Gissel, Hanne; Hojman, Pernille;

    2012-01-01

    Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill...... in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP......, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment...

  19. Tumor necrosis factor-alfa and interleukin-4 in cerbrospinal fluid and plasma in different clinical forms of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Obradović Dragana

    2012-01-01

    Full Text Available Background/Aim. Multiple sclerosis (MS is an immunemediated central nervous system disease characterized by inflammation, demyelination and axonal degeneration. Cytokines are proven mediators of immunological process in MS. The aim of this study was to investigate whether there is a difference in the production of the tumor necrosis factor alpha (TNF-alpha and interleukin-4 (IL-4 in cerebrospinal fluid (CSF and plasma in the MS patients and the controls (other neurological non-inflammatory diseases and to determine a possible difference in these cytokines in plasma and CSF in different clinical forms of MS. Methods. This study involved 60 consecutive MS patients - 48 patients with relapsing-remitting MS (RRMS and 12 patients with secondary progressive MS (SPMS. The control group consisted of 20, age and sex matched, nonimmunological, neurological patients. According to the clinical presentation of MS at the time of this investigation, 34 (56.7% patients had relapse (RRMS, 14 (23.3% were in remission (RRMS, while the rest of the patients, 12 (20.0%, were SPMS. TNF-alpha and IL-4 concentrations were measured in the same time in CSF and plasma in the MS patients and the controls. Extended disability status score (EDSS, albumin ratio and IgG index were determined in all MS patients. Results. The MS patients had significantly higher CSF and plasma levels of TNF-alpha than the controls (p < 0.001 for both samples. IL-4 CSF levels were significantly lower in the MS patients than in the controls (p < 0.001, however plasma levels were similar. The patients in relapse (RRMS and with progressive disease (SPMS had higher concentrations of CSF TNF-alpha levels than the patients in remission (p < 0.001. IL-4 CSF levels in relapse (RRMS and SPMS groups were lower than in the patients in remission. The patients in remission had an unmeasurable plasma TNF-alpha level and the patients with SPMS had significantly lower IL-4 levels in plasma than the patients in

  20. Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy.

    Science.gov (United States)

    Jiang, Xi; Deng, Ke-Qiong; Luo, Yuxuan; Jiang, Ding-Sheng; Gao, Lu; Zhang, Xiao-Fei; Zhang, Peng; Zhao, Guang-Nian; Zhu, Xueyong; Li, Hongliang

    2015-08-01

    Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process.

  1. NANOCOMPOSITE COMPLEX EMAP II INFLUENCE ON TUMOR NECROSIS FACTOR AND INTERFERON

    Directory of Open Access Journals (Sweden)

    L. A. Kolomiets-Babenko

    2016-10-01

    Full Text Available The goal of the research was to determine the ability of new nanocomposite preparation EMAP II (endothelial monocyte activating poplypeptide II to affect the expression of the tumor-necrosis factor and interferon in vitro. In the experiments, the transformed cell line L929 cells was used. The induced interferon levels were determined in samples of culture medium by the microtitration method in the L929 cell culture against test virus vesicular stomatitus VSV. Toxicity of the substance was assessed by its maximum tolerated dose. The amount of endotoxins in nanocomposite preparation EMAP II was measured using gel-clot test. The range of concentrations of EMAP II causing the production of tumor necrosis factor was determined. The concentration of lipopolysaccharides in the tested nanocomposite preparation was less then 0.5 IEU/kg. New nanocomposite preparation EMAP II has the ability to induce TNF-α production at rather low concentration 1.56–25.00 μg/ml (82.49–1370.00 mol х 10–12. The interferon production under the influence of nanocomposite preparation EMAP II was not found. The results support the application of the target nanocomposite reparation EMAP II for cancer treatment.

  2. Recombinant human erythropoietin alpha improves the efficacy of radiotherapy of a human tumor xenograft, affecting tumor cells and microvessels

    Energy Technology Data Exchange (ETDEWEB)

    Loevey, J. [Dept. of Radiotherapy, National Inst. of Oncology, Budapest (Hungary); Bereczky, B.; Gilly, R.; Kenessey, I.; Raso, E.; Simon, E.; Timar, J. [Dept. of Tumor Progression, National Inst. of Oncology, Budapest (Hungary); Dobos, J. [Dept. of Tumor Progression, National Inst. of Oncology, Budapest (Hungary); National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); Vago, A. [Central Lab., National Inst. of Oncology, Budapest (Hungary); Kasler, M. [Head and Neck Surgery, National Inst. of Oncology, Budapest (Hungary); Doeme, B. [National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); Tovari, J. [National Koranyi Inst. of TBC and Pulmonology, Budapest (Hungary); 1. Inst. of Pathology and Experimental Cancer Research, Semmelweis Univ., Budapest (Hungary)

    2008-01-15

    Background and purpose: tumor-induced anemia often occurs in cancer patients, and is corrected by recombinant human erythropoietins (rHuEPOs). Recent studies indicated that, besides erythroid progenitor cells, tumor and endothelial cells express erythropoietin receptor (EPOR) as well; therefore, rHuEPO may affect their functions. Here, the effect of rHuEPO{alpha} on irradiation in EPOR-positive human squamous cell carcinoma xenograft was tested. Material and methods: A431 tumor-bearing SCID mice were treated from the tumor implantation with rHuEPO{alpha} at human-equivalent dose. Xenografts were irradiated (5 Gy) on day 14, and the final tumor mass was measured on day 22. The systemic effects of rHuEPO{alpha} on the hemoglobin level, on tumor-associated blood vessels and on hypoxia-inducible factor-(HIF-)1{alpha} expression of the tumor xenografts were monitored. The proliferation, apoptosis and clonogenic capacity of A431 cancer cells treated with rHuEPO{alpha} and irradiation were also tested in vitro. Results: in vitro, rHuEPO{alpha} treatment alone did not modify the proliferation of EPOR-positive A431 tumor cells but enhanced the effect of irradiation on proliferation, apoptosis and clonogenic capacity. In vivo, rHuEPO{alpha} administration compensated the tumor-induced anemia in SCID mice and decreased tumoral HIF-1{alpha} expression but had no effect on tumor growth. At the same time rHuEPO{alpha} treatment significantly increased the efficacy of radiotherapy in vivo (tumor weight of 23.9 {+-} 4.7 mg and 34.9 {+-} 4.6 mg, respectively), mediated by increased tumoral blood vessel destruction. Conclusion: rHuEPO{alpha} treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1{alpha} expression, but also by destroying tumoral vessels. (orig.)

  3. Pleural tuberculosis in patients with early HIV infection is associated with increased TNF-alpha expression and necrosis in granulomas.

    Directory of Open Access Journals (Sweden)

    Juanita Bezuidenhout

    Full Text Available Although granulomas may be an essential host response against persistent antigens, they are also associated with immunopathology. We investigated whether HIV co-infection affects histopathological appearance and cytokine profiles of pleural granulomas in patients with active pleural tuberculosis (TB. Granulomas were investigated in pleural biopsies from HIV positive and negative TB pleuritis patients. Granulomas were characterised as necrotic or non-necrotic, graded histologically and investigated for the mRNA expression of IL-12, IFN-gamma, TNF-alpha and IL-4 by in situ hybridisation. In all TB patients a mixed Th1/Th2 profile was noted. Necrotic granulomas were more evident in HIV positive patients with a clear association between TNF-alpha and necrosis. This study demonstrates immune dysregulation which may include TNF-alpha-mediated immunopathology at the site of disease in HIV infected pleural TB patients.

  4. Recombination Mutant Human Tumor Necrosis Factor Combined with Chemotherapy in the Treatment of Advanced Cancer

    Institute of Scientific and Technical Information of China (English)

    LIUXing; ZHANGXiangfu; ZHENGZhiweng; LUHuishan; WUXinyuan; HUANGChangmin; WANGChuan; GUANGuoxian

    2005-01-01

    Objective: Past studies showed that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. The objective of present study is to evaluate the therapeutic effects and adverse reactions of recombinant mutant human tumor necrosis factor (rmhTNF) combined with chemotherapy in patients with advanced malignant tumor. Methods: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients.rm hTNF was injected intramuscularly to the trial group at a dose of 4×106 U/m2, from the 1st to 7th days, the llth to 17th days combined with chemotherapy course. The chemotherapy plan was as follows:CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. Results: In the trial group there was 1 CR case and 12 PR cases, and the response rate was 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate in the trial group was significantly higher than that in the control group (P=0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those in the control groups. After the treatment the KPS was 89.00+9.92 in the trial group,and 84.17±8.84 in the control group, with a significant difference between the two groups (P=0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable

  5. Use of the tumor necrosis factor-blockers for Crohn's disease

    Institute of Scientific and Technical Information of China (English)

    Alan BR Thomson; Milli Gupta; Hugh J Freeman

    2012-01-01

    The use of anti-tumor necrosis factor-α therapy for inflammatory bowel disease represents the most important advance in the care of these patients since the publication of the National Co-operative Crohn's disease study thirty years ago.The recommendations of numerous consensus groups worldwide are now supported by a wealth of clinical trials and several meta-analyses.In general,it is suggested that tumor necrosis factor-α blockers (TNFBs) are indicated (1)for persons with moderately-severe Crohn's disease or ulcerative colitis (UC) who have failed two or more causes of glucocorticosteroids and an acceptably long cause (8 wk to 12 wk) of an immune modulator such as azathioprine or methotrexate; (2) non-responsive perianal disease; and (3) severe UC not responding to a 3-d to 5-d course of steroids.Once TNFBs have been introduced and the patient is responsive,therapy given by the IV and SC rate must be continued.It remains open to definitive evidence if concomitant immune modulators are required with TNFB maintenance therapy,and when or if TNFB may be weaned and discontinued.The supportive evidence from a single study on the role of early versus later introduction of TNFB in the course of a patient's illness needs to be confirmed.The risk/benefit profile of TNFB appears to be acceptable as long as the patient is immunized and tested for tuberculosis and viral hepatitis before the initiation of TNFB,and as long as the long-term adverse effects on the development of lymphoma and other tumors do not prone to be problematic.Because the rates of benefits to TNFB are modest from a population perspective and the cost of therapy is very high,the ultimate application of use of TNFBs will likely be established by cost/benefit studies.

  6. The functional tumor necrosis factor-α (308A/G) polymorphism modulates attentional selection in elderly individuals.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2013-11-01

    There has been increasing interest in understanding the role of inflammatory processes for cognitive functions in aging using molecular genetic approaches. Though this has mostly been evaluated in pathological aging, little is known about the relevance for cognitive functions in healthy aging in humans. On the basis of behavioral data and neurophysiological data (event-related potentials and time-frequency decomposition) we show that the A-allele of the functional tumor necrosis factor (TNF)-α -308 A/G polymorphism confers dysfunction in a number of cognitive processes: prolonged attentional selection indexed by a delayed P1/N1 complex, an increased P3a, which is interpreted as an enhanced distractibility by nonrelevant stimuli and compromised response selection mechanisms, as indexed by a reduced frontocentral N2. Time-frequency analyses show that allelic variations further exert their effects by modulating alpha and beta frequency oscillations. On a neurobiological level, these effects might be because of the interaction of TNF-α with glutamatergic neural transmission by which TNF-α is known to boost apoptotic mechanisms in elderly individuals.

  7. Tumor Necrosis Factor (TNF-alpha) Treatment of Ankylosing Spondylitis Clinical Adverse Reactions Observed%肿瘤坏死因子拮抗剂(TNF-α)治疗强直性脊柱炎临床不良反应观察

    Institute of Scientific and Technical Information of China (English)

    徐刚

    2012-01-01

      Objective:To learn about the common and the rare adverse reactions taking place in the clinical treatment of ankylosing spondylitis with tumor necrosis factor (TNF) antagonist.Method:50 cases of patients were enrolled in this group receiving TNF antagonist (the product used in this group was Etanercept from Shanghai CP Guojian Pharmaceutical Co,Ltd) for treating ankylosing spondylitis.In addition,the incidence of adverse reactions and the common reverse reactions were observed.Result:Of the 50 patients received TNF antagonist for treating ankylosing spondylitis,first-dosage adverse reactions occurred in eight cases and medium or long-term adverse reactions occurred in 5 cases.Conclusion:The usage of biological agent in the treatment of ankylosing spondylitis is considered as a safe and efficacious approach,in which the occurrence and management of the adverse reactions should be concerned.%  目的:了解接受肿瘤坏死因子拮抗剂治疗强直性脊柱炎临床常见不良反应及少见不良反应。方法:本组选取了50例强直性脊柱炎患者接受肿瘤坏死因子拮抗剂(本组均选用上海中信科健公司产品益赛普)治疗,同时观察不良反应发生率及常见不良反应症状。结果:接受肿瘤坏死因子拮抗剂治疗的50例患者发生首次不良反应的有8例,中长期不良反应5例。结论:生物制剂治疗强直性脊柱炎是安全有效的,但应注意不良反应的发生及处置。

  8. The Relationship between Plasma Tumor Necrosis Factor and Pneumonia of Tibetan Neonates

    Institute of Scientific and Technical Information of China (English)

    ZHOU Cuojie; DEJI Meiduo; ZHAO Min

    2002-01-01

    This study was to discuss the changing characteristics of plasma tumor necrosis factor (TNF) in Tibetan neonates with pneumonia. Radioimmunoassay was applied to determine the plasma level of TNF in 48 tibetan neonates with pneumonia and 20 healthy term newborns. The results showed that the plasma level of TNF in severe group with pneumonia( 16.075 ± 13. 1603ug/mt) was higher than that in mild group(14.705 ± 13.0162), P < 0.001. The TNF level of these two groups were significantly higher than that of healthy control group(7. 8650 ± 2. 5173ug/mt), P < 0. 001. So, the plasma level of TNF was closely related with the severity of pneumonia. Severer pneumonia was, higher TNF level was.It suggested that TNF was involved in the regulating process in pneumonia.

  9. Tumor Necrosis Factor and Lymphotoxin-α Polymorphisms and Severe Malaria in African Populations

    Science.gov (United States)

    Clark, Taane G.; Diakite, Mahamadou; Auburn, Sarah; Campino, Susana; Fry, Andrew E.; Green, Angela; Richardson, Anna; Small, Kerrin; Teo, Yik Y.; Wilson, Jonathan; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Griffiths, Michael J.; Peshu, Norbert; Williams, Thomas N.; Marsh, Kevin; Molyneux, Malcolm E.; Taylor, Terrie E.; Rockett, Kirk A.; Kwiatkowski, Dominic P.

    2009-01-01

    The tumor necrosis factor gene (TNF) and lymphotoxin-α gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving > 10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF −238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms. PMID:19281305

  10. Protective effects of tumor necrosis factor antibody and ulinastatin on liver ischemic reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Ling Yang; Ji-Peng Li; Xiao-Ping Xu; Ke-Feng Dou; Shu-Qiang Yue; Kai-Zong Li

    2004-01-01

    AIM: To study the protective effects of tumor necrosis factor α(TNFα) antibody and ulinastatin on liver ischemic reperfusion in rats.METHODS: One hundred and twenty male SD rats were randomly divided into four groups: normal control group,ischemic group, TNFα antibody group and TNFα antibody + ulinastatin group. The animals were killed at 0, 3, 6, 9,12 h after ischemia for 60 min and followed by reperfusion.Serum alanine aminotransferase (ALT), malondialdehyde (MDA) and liver histopathology were observed.RESULTS: After ischemic reperfusion, the serum ALT and MDA were remarkably increased, and the hepatic congestion was obvious. Treatment of TNFα antibody and ulinastatin could significantly decrease serum ALT and MDA levels,and relieve hepatic congestion.CONCLUSION: Ulinastatin and TNFα antibody can suppress the inflammatory reaction induced by hepatic ischemic reperfusion, and have protective effects on rat hepatic ischemic reperfusion injury.

  11. Tumor necrosis factor α antibody prevents brain damage of rats with acute necrotizing pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Yan-Ling Yang; Ji-Peng Li; Kai-Zong Li; Ke-Feng Dou

    2004-01-01

    AIM: To study the protective effects of tumor necrosis factor á (TNFα) antibody on pancreatic encephalopathy in rats.METHODS:One hundred and twenty SD rats were randomly divided into normal control group,acute necrotizing pancreatitis group and TNFα antibody treated group.Acute hemorrhage necrotizing pancreatitis model in rats was induced by retrograde injection of 50 g/L sodium taurocholate into the pancreatobiliary duct.Serum TNFα was detected and animals were killed 12 h after drug administration.Changes in content of brain water,MDA and SOD as well as leucocyte adhesion of brain microvessels were measured.RESULTS:In TNFα antibody treated group,serum TNFálevel was decreased.Content of brain water,MDA and SOD as well as leucocyte adhesion were decreased significantly in comparison with those of acute necrotizing pancreatitis group (P<0.05).CONCLUSION:TNFα antibody can alleviate the brain damage of rats with acute hemorrhage necrotizing pancreatitis.

  12. Mechanism of inhibition of HSV-1 replication by tumor necrosis factor and interferon gamma.

    Science.gov (United States)

    Feduchi, E; Carrasco, L

    1991-02-01

    Tumor necrosis factor (TNF) synergizes with interferon (IFN gamma) in the blockade of HSV-1 replication. Antibodies against IFN beta block this synergism, implying a role of IFN beta in the antiviral activity of TNF plus IFN gamma. IFN beta 1 added exogenously to Hep-2 cells shows antiviral activity against HSV-1 only at high concentrations, whereas IFN beta 2 (also known as IL-6) alone has no effect on the replication of VSV or HSV-1 even when 1,000 U/ml are present. Our results are in accordance with the idea that TNF induces IFN beta 1 and that both cytokines must be present in the culture medium to synergize with IFN gamma in order to inhibit HSV-1 replication.

  13. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Olesen, Caroline Meyer; Coskun, Mehmet; Peyrin-Biroulet, Laurent

    2016-01-01

    Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural...... differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy...... is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF...

  14. Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis.

    Science.gov (United States)

    Atzeni, Fabiola; Costa, Luisa; Caso, Francesco; Scarpa, Raffaele; Sarzi-Puttini, Piercarlo

    2015-11-01

    Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents.

  15. New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol.

    Science.gov (United States)

    Cauli, Alberto; Piga, Matteo; Lubrano, Ennio; Marchesoni, Antonio; Floris, Alberto; Mathieu, Alessandro

    2015-11-01

    The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-α (TNF-α) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-α activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.

  16. Formation of Ion-Permeable Channels by Tumor Necrosis Factor-α

    Science.gov (United States)

    Kagan, Bruce L.; Baldwin, Rae Lynn; Munoz, David; Wisnieski, Bernadine J.

    1992-03-01

    Tumor necrosis factor-α (TNF, cachectin), a protein secreted by activated macrophages, participates in inflammatory responses and in infectious and neoplastic disease states. The mechanisms by which TNF exerts cytotoxic, hormonal, and other specific effects are obscure. Structural studies of the TNF trimer have revealed a central pore-like region. Although several amino acid side chains appear to preclude an open channel, the ability of TNF to insert into lipid vesicles raised the possibility that opening might occur in a bilayer milieu. Acidification of TNF promoted conformational changes concordant with increased surface hydrophobicity and membrane insertion. Furthermore, TNF formed pH-dependent, voltage-dependent, ion-permeable channels in planar lipid bilayer membranes and increased the sodium permeability of human U937 histiocytic lymphoma cells. Thus, some of the physiological effects of TNF may be elicited through its intrinsic ion channel-forming activity.

  17. Unusual location of tuberculosis in the course of tumor necrosis factor α inhibitor therapy.

    Science.gov (United States)

    Bielewicz-Zielińska, Agnieszka; Brzezicki, Jan; Rymko, Marcin; Jeka, Sławomir

    2015-01-01

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis complex mycobacteria. Extrapulmonary tuberculosis usually develops more than two years after infection or many years later. Factors favoring onset of the disease are malnutrition, older age, renal failure, diabetes, cancer, immunosuppression and biological treatment, e.g. tumor necrosis factor α (TNF-α) inhibitors. The paper presents a case of a 56-year-old patient with ankylosing spondylitis treated with infliximab, diagnosed with tuberculosis of the spleen. The unusual location and uncharacteristic symptoms created a lot of diagnostic difficulties, particularly as during qualification for biological treatment tests are performed to exclude infection with Mycobacterium tuberculosis. Pharmacological treatment of tuberculosis is typical, but in the case of tuberculosis of the spleen, splenectomy also is a method of treatment. The decision was made to implement pharmacological treatment, which proved to be effective, so the patient avoided surgery.

  18. Structural requirements for inducible shedding of the p55 tumor necrosis factor receptor

    DEFF Research Database (Denmark)

    Brakebusch, C; Varfolomeev, E E; Batkin, M

    1994-01-01

    Induced shedding of the p55 tumor necrosis factor receptor (p55-R) was previously shown to be independent of the amino acid sequence properties of the intracellular domain of this receptor. We now find it also independent of the sequence properties of the transmembrane domain and of the cysteine......-rich region that constitutes most of the extracellular domain of the receptor. The shedding is shown to depend solely on the sequence properties of a small region within the spacer that links the cysteine-rich region in the extracellular domain to the transmembrane domain. Detailed tests of effects......, however, by some mutations that seem to change the conformation of the spacer region. These findings suggest that a short amino acid sequence in the p55-R is essential and sufficient for its shedding and that the shedding is mediated either by a protease with limited sequence specificity or by several...

  19. [Tumor necrosis factor alfa in cardiovascular diseases: molecular biology and genetics].

    Science.gov (United States)

    Fragoso Lona, José Manuel; Sierra Martínez, Mónica; Vargas Alarcón, Gilberto; Barrios Rodas, Angélica; Ramírez Bello, Julián

    2013-01-01

    Cardiovascular diseases are a major public health problem globally. In 1997, cardiovascular disease caused 41% of deaths in the United States. It has been reported that about 60 million people in the United States have some form of cardiovascular disease. These entities are chronic conditions initiated by a dysregulation of the immune response. One gene and its protein product -tumor necrosis factor a (TNF-α)- a powerful pleiotropic cytokine with multiple cellular functions, plays a role in the inflammation, initiation, development, susceptibility, severity, and response to treatment, etc. of coronary artery disease (CAD). The focus of the present review is to summarize recent evidence showing the biological role of TNF-α in the initiation and progression of endothelial dysfunction and complications of atherosclerosis, and as a genetic variation of TNF-α confer susceptibility, severity, and treatment response in CAD: ST-segment elevation myocardial infarction and non-ST segment elevation myocardial infarction, unstable angina, and coronary restenosis.

  20. Interferon and tumor necrosis factor as humoral mechanisms coupling hematopoietic activity to inflammation and injury.

    Science.gov (United States)

    Askenasy, Nadir

    2015-01-01

    Enhanced hematopoiesis accompanies systemic responses to injury and infection. Tumor necrosis factor (TNF) produced by injured cells and interferons (IFNs) secreted by inflammatory cells is a co-product of the process of clearance of debris and removal of still viable but dysfunctional cells. Concomitantly, these cytokines induce hematopoietic stem and progenitor cell (HSPC) activity as an intrinsic component of the systemic response. The proposed scenario includes induction of HSPC activity by type I (IFNα/β) and II (IFNγ) receptors within the quiescent bone marrow niches rendering progenitors responsive to additional signals. TNFα converges as a non-selective stimulant of HSPC activity and both cytokines synergize with other growth factors in promoting differentiation. These physiological signaling pathways of stress hematopoiesis occur quite frequent and do not cause HSPC extinction. The proposed role of IFNs and TNFs in stress hematopoiesis commends revision of their alleged involvement in bone marrow failure syndromes.

  1. NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor (TNF alpha) region in primary biliary cirrhosis and in healthy Danes

    DEFF Research Database (Denmark)

    Fugger, L; Morling, N; Ryder, L P;

    1989-01-01

    The restriction fragment length polymorphism of the human tumour necrosis factor (TNF alpha) region was investigated by means of 20 different restriction enzymes and a human TNF alpha cDNA probe. Only one of the enzymes, NcoI, revealed a polymorphic pattern consisting of fragments of 10.5 and 5...

  2. GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus.

    Science.gov (United States)

    Das, U N

    1999-01-01

    It is now believed that the GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes have an important role in the development of obesity and non-insulin dependent diabetes mellitus (NIDDM). The protein encoded by daf-2 is 35% identical to the human insulin receptor, daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 can enhance superoxide dismutase (SOD) expression. EFAs and their metabolites can alter the cell membrane fluidity and enhance the expression of GLUT-4 and insulin receptors. EFAs can suppress TNF-alpha production and secretion, a mechanism that may have relevance to the role of these fatty acids in the pathogenesis of insulin resistance, obesity and NIDDM. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Based on this evidence, it is proposed that GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin interact with each other in ways which may have relevance to the development or abrogation of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.

  3. Eupatilin protects against tumor necrosis factor-α-mediated inflammation inhuman umbilical vein endothelial cells.

    Science.gov (United States)

    Yu, Kai; Li, Xi-Ming; Xu, Xiao-Lei; Zhang, Ru-Yan; Cong, Hong-Liang

    2015-01-01

    Inflammatory responses in the blood vessel play a pivotal role in the pathogenesis of atherosclerosis. Eupatilin, a flavone derived from Artemisia princepsPampanini, has various pharmacological activities, including antioxidant, anti-tumor, and anti-inflammatory capacities. However, there has been no research examining the function of eupatilin on vascular inflammation. Therefore, the aim of this study was to investigate the effects of eupatilin on tumor necrosis factor (TNF)-α-induced human umbilical vein endothelial cells (HUVECs) activation and the underlying molecular mechanisms. Our findings showed that eupatilin reduced U937 cells adhesion to TNF-α-stimulated HUVECs and attenuated TNF-α-induced the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in HUVECs, as well as the production of intracellular reactive oxygen species (ROS). Moreover, eupatilininhibits TNF-α-induced phosphorylation of NF-kB p65 and MAPKs in HUVECs. Taken together, the results of the present study suggest that eupatilin inhibited inflammatory reaction through suppressing the ROS/MAPK-NF-ĸB pathway in HUVECs. Thus, eupatilin is proposed as an effective new anti-inflammatory agent to suppress vascular inflammation, and further prevent atherosclerosis.

  4. Tumor Necrosis Factor (TNF) and Chemokines in Colitis-Associated Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Mukaida, Naofumi, E-mail: naofumim@kenroku.kanazawa-u.ac.jp; Sasakki, So-ichiro [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Popivanova, Boryana K. [Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Present Address, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2011-06-27

    The connection between inflammation and tumorigenesis has been well established, based on a great deal of supporting evidence obtained from epidemiological, pharmacological, and genetic studies. One representative example is inflammatory bowel disease, because it is an important risk factor for the development of colon cancer. Moreover, intratumoral infiltration of inflammatory cells suggests the involvement of inflammatory responses also in other forms of sporadic as well as heritable colon cancer. Inflammatory responses and tumorigenesis activate similar sets of transcription factors such as NF-κB, Stat3, and hypoxia inducible factor and eventually enhances the expression of inflammatory cytokines including tumor necrosis factor (TNF) and chemokines. The expression of TNF and chemokines is aberrantly expressed in a mouse model of colitis-associated carcinogenesis as well as in inflammatory bowel disease and colon cancer in humans. Here, after summarizing the presumed actions of TNF and chemokines in tumor biology, we will discuss the potential roles of TNF and chemokines in chronic inflammation-associated colon cancer in mice.

  5. Evaluation of dynamic contrast-enhanced T1-weighted perfusion MRI in the differentiation of tumor recurrence from radiation necrosis

    DEFF Research Database (Denmark)

    Larsen, Anne Vibeke Andrée; Simonsen, Helle J; Law, Ian;

    2013-01-01

    INTRODUCTION: To investigate if perfusion measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to differentiate radiation necrosis from tumor recurrence in patients with high-grade glioma. METHODS: The study was approved by the institutional review board...

  6. The relationship between tumor necrosis factor-α gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome

    Institute of Scientific and Technical Information of China (English)

    刘辉国

    2006-01-01

    Objective To investigate the relationship between tumor necrosis factor-α(TNF-α) gene promoter polymorphism and obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods The plasma TNF-αlevel of OSAHS group and non-OSAHS group was detected by enzyme-linked immunosorbent assay (ELISA). Eighteen patients with severe OSAHS were treated with continuous

  7. Nitric oxide-releasing agents enhance cytokine-induced tumor necrosis factor synthesis in human mononuclear cells

    NARCIS (Netherlands)

    Eigler, A; Sinha, B; Endres, S

    1993-01-01

    In septic shock tumor necrosis factor (TNF) leads to increased nitric oxide (NO) production by induction of NO synthase. An inverse regulatory effect, the influence of NO on cytokine synthesis, has rarely been investigated. The present study assessed the influence of NO-releasing agents on TNF produ

  8. Differential sensitivity of hormone-responsive and unresponsive human prostate cancer cells (LNCaP) to tumor necrosis factor

    NARCIS (Netherlands)

    X. Zhao (X.); G.J. van Steenbrugge (Gert Jan); F.H. Schröder (Fritz)

    1992-01-01

    textabstractTwo sublines, the hormone-sensitive LNCaP-FGC and the insensitive LNCaP-r (resistant) carcinoma cell lines, originating from the parental human prostatic carcinoma cell line LNCaP were tested for sensitivity to human tumor necrosis factor-α (TNF) using the MTT assay. Irrespective of the

  9. Tumor necrosis factor-α and receptor activator of nuclear factor-κB ligand augment human macrophage foam-cell destruction of extracellular matrix through protease-mediated processes

    DEFF Research Database (Denmark)

    Skjøt-Arkil, Helene; Barascuk, Natasha; Larsen, Lise;

    2012-01-01

    component of extracellular matrix (ECM) in plaques, and to establish whether the pro-inflammatory molecules, tumor necrosis factor (TNF)-alpha, and receptor activator of nuclear factor-κB ligand (RANK-L) increase this degradation. CD14+ monocytes isolated from peripheral blood were differentiated......% and 72%, respectively. This is, to our knowledge, the first data describing a simple in vitro system in which macrophage foam cells degradation of matrix proteins can be monitored. This degradation can be enhanced by cytokines since TNF-alpha and RANK-L significantly increased the matrix degradation...

  10. Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases From a Single Institution.

    Science.gov (United States)

    Khor, Li-Yan; Dhakal, Hari P; Jia, Xuefei; Reynolds, Jordan P; McKenney, Jesse K; Rini, Brian I; Magi-Galluzzi, Cristina; Przybycin, Christopher G

    2016-09-01

    Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (PISUP grade could be further prognostically

  11. Pharmacological analysis for mechanisms of GPI-80 release from tumour necrosis factor-alpha-stimulated human neutrophils.

    Science.gov (United States)

    Nitto, Takeaki; Araki, Yoshihiko; Takeda, Yuji; Sendo, Fujiro

    2002-10-01

    1 GPI-80, a glycosylphosphatidylinositol (GPI)-anchored protein initially identified on human neutrophils, plays a role(s) in the regulation of beta2 integrin function. Previous studies have shown that GPI-80 is sublocated in secretory vesicles. It is also found in soluble form in the synovial fluid of rheumatoid arthritis patients, and in the culture supernatant of formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils. To understand the behaviour of GPI-80 under conditions of stimulation, we investigated the effects of tumour necrosis factor (TNF)-alpha on its expression and release. We also probed the mechanism of its release with various pharmacologic tools. 2 TNF-alpha induced the release of GPI-80 from human neutrophils in a concentration- and time-dependent manner (in the range of 1-100 u ml(-1) and 30-120 min, respectively), but did not affect surface GPI-80 levels. 3 Cytochalasin B, genistein, and SB203580 but not PD98059 inhibited TNF-alpha-stimulated GPI-80 release and neutrophil adherence at the same concentration. In addition, TNF-alpha-induced GPI-80 release was inhibited by blocking monoclonal antibodies specific to components of Mac-1 (CD11b and CD18). 4 Antioxidants (pyrrolidine dithiocarbamate and N-acetyl-L-cysteine) inhibited GPI-80 release by TNF-alpha stimulation, but superoxide dismutase did not. Antioxidants but not superoxide dismutase reduced an intracellular oxidation state. 5 These findings indicate that TNF-alpha-stimulated GPI-80 release from human neutrophils depends upon adherence via beta2 integrins. They also suggest that cytochalasin B, genistein, and SB203580 inhibit GPI-80 release by suppressing signals for cell adherence, rather than by a direct effect on its secretion. Finally, we suggest that GPI-80 release involves an intracellular change in a redox state.

  12. Clinical Response, Drug Survival, and Predictors Thereof Among 548 Patients With Psoriatic Arthritis Who Switched Tumor Necrosis Factor α Inhibitor Therapy

    DEFF Research Database (Denmark)

    Glintborg, Bente; Ostergaard, Mikkel; Krogh, Niels Steen;

    2013-01-01

    To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care.......To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care....

  13. 体外培养APA微囊化肿瘤坏死因子α/293细胞对结肠癌细胞增殖的影响%Tumor necrosis factor alpha-sercreting microcysts inhibit proliferation of Lovo colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    高宇红; 彭瑞云

    2011-01-01

    BACKGROUND: This study was designed to establish gene engineered cells which auto-secreting human tumor necrosis factor-a (TNF-a). Alginate-polylysine-alginate (APA) microencapsulated cells were co-cultured with colon cancer cells. On the one hand, the effects of micro -biological pump could be exerted to continously secrete TNF-a in the intracapsule cells. On the other hand, the immune rejection-prevented effects of APA microcapsules could be exerted to limit the overgrowth of highly-proliferative intracapsule cells. OBJECTIVE: To explore the effects of co-culture of TNFa-sercreting microcysts and human colon cancer cells Lovo on the proliferation of cancer cells.METHODS: Former established method was used. APA m